Clinicel PharmKOkinetics 1: 2-24 (1976) Cl AD1S PrHl1976

Clinical Pharmacokinetics in Infants and Children

A. Rane and J. T. Wilson Department of Clinical Pharmacology lit the Kllrolinska Institute (Huddinge Univer1ity Hotpital), Stockholm, lind Division of Pediatric Clinical PhlllTTllICology, Departments of Pediatrics and PharmllCoIogy, Vanderbilt Univer1ity School of Medicine, NlIShville, Tennes5ee

Summary

Wide vtlrUltions in drug dose reoommencllltions for children of the same or different ages reflect the inudeqlUlCJ' of dota 011 pharmoookinetio and pharmooodyrwmicr in children. Selected as~cts of am/wble IiteTf1ture on pliarmaookinericr of drugs uud in older infants and children has bun relliewed with speciDl attention to Ctllcukltion of an ageoDpproprUlte dose. During the neonatal period and early infancy the efimirwtion of rtUlny drugs that are excreted in the urille /n unchonged form is restricted by th e immoturity of glomerulor fi/tTf1tiOll and reno/ rubu/or secretion. On the other hand. in /ote infoncy (lIldlor in chi/dhood, a nmi/or or greuUr rate of elimirwlion from plosmo thon in adults ho s been obserl'ed for many drugs, notably digoxin. pheno/Jorbitone, phenytoin, Ctlr/Jomozepine. etho$llxi. midi!, diozoxide, dindomydn ond propoxypheni!, Consistent with this. it hDs been sho wn thor $lOme drugs exhibit a/ower pwsmo {elle/ldose Tf1tlo in infoncy and eor/y childJrood as oomptIred with the udult. This is true for phenobarbitone, pheny toin and ethosuximide. Some oge groups of children remoin IlI1investigated with regard to pharmocokinetics, ellen for the drugs reviewed. 71lerefore, pediatric therapy remains empiriCtllly based for many drugs.

Until some 15 to 20 years ago, drug dosing in infants and children was empirically based on and guided by different rules utilising weight , age or body surface area as the basis for calculating the child's dose as a fraction of the adult dose. None of Ihese rules is ideal although the body surface area seems to be more applicable as a basis for determining the drug dosage than any of the other suggested methods. The body surface area corre· lates to a number of physiologic parame ters which

have importance for drug kinetics. I With the development of analytical methods for many drugs, it became possible to monitor pha rmacothe rapy by measuring Ihe drug levels in plasma or blood. Concomitantly, pharmacokinetic principles Body surface area correlate$ with the weight to the 0.7 power and according to this rule the dose for the child equal.lweight of chi ld/701, '0.7 lluuming the adult weight i.70kg.

Oinicel PI'Iarmilcokinetics in Infants and Children

have been more and more used for the prediction of drug doses that will give optimum plasma concentrations in patients. Paediatric drug therapy , and especially dose calculation, is complicated by the continuous change in body w-eight and body composition during infancy and childhood. The relative weigh t of various tissues and organs changes during the development are shown in figure I. Naturally, such changes may significant ly influence the relative disposition of drugs and the ir side-effects . Differences in the pharmacodynamic effects of dru~ in children and adults may also complicate the paediatric use of drugs. The pharmacodynamic aspects of drugs in infancy and childhood have received very little attention. 11lese difficulties are compounded by the fact that many new drugs, when released on the market , are largely untried in children and have been investigated predominately in adults. This is reflected by the sparse recommendations for

200

180

Lvmphoid type,,.'"",, , ,

,

, ,,

160

100

80

~

l

/

20

\

I ,,

120

60 40

,

/

140

~

,, ,

\

,,

/ :;;;" "po " " '"" ,"General /I I type

I

/ I

/

~V---_._.-

Genital type ./ /1

4 Age

8

12

16

20

Ivears)

Fig. I. Relative lizes of di fferent orga n types during development (aft'" Nehon et al.: Textbook 0 1 Pedia trics, Sau nders, Philadelphia 1975; with per m ission ).

3

paediatric drug dosing in the pharmaceutical reference literature (Wuson, 1975a). The refore, CO nl ribut ions to the paed iatric clinical pharmacological research field have been welcomed by clinicians who must treat children with drugs . The clinical usefulness of even the most precisely described pharmacokinetics for any drug at any age is weakened by compliance failu re. Patients seldom take dru~ as directed (Wilson, 1973). Becker (1972) has highlighted some of the prognostic risk fac tors of compliance fa ilure for parents charged with drug administration to children on an out-patient basis. However, compliance failure also occurs in the hospital setting (Wilson and Wilkinson, 1974; Wilson, 1976). Failure to adequately appreciate the extent of compliance problems can lead to chronic underdosing or, with sudden improvement in compliance, toxicity from overdOSing. Interpretation of plasma level data and adequate utilisation of pharmacokinetic data must depend upon knowledge of compliance in the par· ticular populat ion of children receiving a drug. 111is review summarises selected aspects of our present knowledge about clinical pharmacokinet ics in infants (except neonates 2 ) and children. Special attention has been devoted to studies with d irect applicability in the clinical situation. To give a background for the presentation, some physiological changes that occur during a child's maturation and that are important for the disposition of drugs are summarised.

I. Developmental Changes in Body Water Compar/menu The total body water (TRW) and its distri bu· tion is entirely different in the newborn and the fully mat ure individual. In newborns, T RW consti· tutes 70 to 75% of the body weight whereas the corresponding value in adults is 50 to 55%. 2 Cli nical pharmacokinet ics in neonate. is the subject of • IeP8rate a~ticle in a forthcoming issue.

•

Clinical Phwrrec:okiMtiCi in Inflnts and Childrln

The extracellular water (ECW) content is also significantly greater in the neonatal pe riod, some 40% as compared with about 20% of body weight in adults when calculated with thiosulphate or inulin (Friis·Hansen, 196 1). Since most drugs dis· tribute throughout the ECW space in order to reach their receptors, the size of the ECW (and other nuid) compartments are of importance for the ultimate drug concentra tion. This is especially true fo r drugs without excessive tissue binding, the real distribution of which is grossly confined to the extracellular nuid space. For such drugs, dosage on the basis of ECW space would be more accurate than on a body weight basis. This is evi· dent from figure 2 which demonstrates the varia· tion of ECW/ kg body weight throughout infancy and childhood. In fact, many drugs are indirectly dosed in relatio n t o ECW since this correlates closely with body surface area. It is also conceivable f ro m the relationship be· tween plasma half·life (t~) and the apparent volume of distribution (Vd) t

0.693

•

- -- -

K..

0.693 ' Vd

(Eq. J)

a

Ke"

(where is the apparent flfst~rder rate con· stant for elimination), that the apparent volume of distribution has innuence on the plasma half·life of drugs. During constant clearance an increased Vd will be associated with an increase in t ~. Clear· ance calculations are preferred since both Kell! and Vd are considered :

(Eq.2)

2. Developmental Changes in the Kidneys Drug Eliminating Processes The low glomerular filtration (GF) rate in new· borns was described a long time ago (West et aI., 1948; Barnett et aI., 1949). Penicillins are excreted via GF and their elimination is capacity.limited by maturation of renal function. Thus , the half·lives of many antibiotics are prolonged in the neonatal period (Axline et a1., 1967 : Barnett et a1., 1949). However, only a limited and early part of infancy is associated with low GF rate. Glomerular filtration attains the adult value (per unit of body sur·

....... .........

,

..

ManlN

,, ,,

. . ,

Ag41~1"1

,

,

" "

,

•

M>lu

FlfI.. 2. Developmentll ChI"911 in l otll bodv Wit .... Intracellullr Ind Ixu_nul ... WIt .... In Inllnts I nd children. Th, ChinVI'''' expr_d II pwcenteges 01 bocty ~I. Oetelrom Frii...... nsen 119611.

•

Clin;ca, Phwmec:okinetia in Inl."".,,d Child,..n

rabl, I. calculation 01 twlll.Jil, lor I proposed l2"ulil with the .. me c;:1_,ne, .. inulin (glomerular liltrltion' or pe ..... mlnohippurlc acid tPAH, tubular te(:fetion' in In infant 11 Y, months o ld) Ind ldult. The drug is lUpposeO to diwibut. In tha .xtrlOlllulw watlt!" ",,101 tECW) . Da ta from West et al. (1948) and Friil· H.n..,n (19611. ty, • 0.693 'Vd· c;:1 ..,.nce- 1 Weight kg

,CW " 01 weight

,-

total vol. ml

Inlant Adult

4.'

10.0

32

'8

'2600

face area) between 2~ and 5 months of age (West et al., 1948). Similarly, the renal tubular secretory capacity , measured as para.aminohippuric acid secretion, increases ove r the first months of life to reach the adult level (per unit of body surface area) at about 7 months (West et ai., 1948). nle development of the renal tubular reabsorbing capacity is largely unknown. With the knowledge of inulin and para-aminohippuric acid clearance in infants and adults, the age·dependent difference in t ~ and clearance can be calculated for drugs that are excreted similarly to these compounds, i.e. via g.lomerular nitration or renal tubular secretion, respectively. Table I shows that the half-lives would be about 50% and 3 times longer in the infant in the case of g.lomerular nitration or tubular secretion, respect ively .

3. Other DevelopmentQI Changes The quantitatively most important organ for drug metabolism is the liver . Apart from its size , which changes with development both relatively and absolutely (Ahman and Dittmer, 1962), the activity of the hepatic drug metabolis.ing enzymes may also be age-dependent. Different studies have shown that it is not possible to generalise about the drug metabolising capacity in newborns since this varies depending on which drug is studied, if

PAH

Inulin Clearance ml·min· 1

t)!omin

CI.....nte ml·min· 1

.bouttO

'00

about 25 650

13.

67

ty, min

4. 13

the newborn was exposed to the drug in utero etc. (Rane et al., 1914; Rane 1914; Sj5qvist et al., 1912). There is no systematic study on this in older children but, for some drugs as indicated below, children have a more rapid elimination than adults, possibly due to increased hepatic metabolic activity. Diurnal variation of drug kinetics has been ob· served for drugs with p H-dependent urinary ex· cretion and non-ionic diffusion. The sleep-awake pattern in infancy is pushed towards more sleep during the 24 hour period than in adults. Infants below 1 year sleep about as much in daytime as at night, and have about the same urinary pH at night as in the day (Krauer, 1975). In older infants and children the periodicity of sleep and wakefulness becomes more biphasic and the urinary pH is more acid at night than in daytime. Acid drug excretion decreases and basic drug excretion increases at low pH, and vice vena. Consistent changes in half·life are obse rved. This has been shown for sulphafurazole (sulfisoxazole) (PKa:: 4 .9), sulfisomidine (PKa:: 7.4), the ha1f·lives of which are prolonged at night by 100 and 40 to 50%, respectively , in children with biphasic adult sleep pattern (Krauer, 1915). Plasma protein binding of drugs may be af· fected by qualitative or quantitative changes of the plasma proteins. Very little is known about such changes during early development. As mentioned below, some drugs are bound to a lesser degree in

6

alnieal PharlTlllC(lkinetics in Infants and Children

TIibI, II. ComperilOn ollheophylline pharmecokinetic parameters in children and adults

Age Iyrl

eo..

OIildfen

.

Ro,·

~11·lilelh) mAO

range

Clearance (mI{h/kg)

Vd

KelliS) (h' l )

Rel&rence

Ufkg)

1931

0.404

0.386

30.&-221 (87)

0.278- 0.519

0.198- 0.80

Maselli ,1970 Ellis .1 aI., 1974 Ell is 81 aI., 1975

3.4mg/kg 3.4mg1kg 4mg/kg

''""

3.0 3.' 3.69

1.2- 10 1.42- 7.85

42.5mgper h lor 22h

;,

~2

3.0--9.5

66

1

19

Jenne, 1972

19- 53

2.4-5.6mgl ;,

4.4

2.9- 7.1

72

1-

18

Mitenko.1973

22- 27

kg 4mg

5.76

3.47- 7.97

39.7- 91.8 (57)

0.342- 0.589

0.158- 0.434

Elli~

21 - 31

260mg

1531

(0.457)

10. 115)

Welling, 1975

4-15 6-17

Adula

1561

'" '"

po

6.3

et al., 1975

I ) . mean value

cord plasma and in infant plasma as compared with adult plasma. Also , drug binding may de· crease in the presence of increased levels of endo· genous compounds, e.g. bilirubin and free fatty acids (Rane et aI., 1971; Fredholm et aI., 1975), probably a result of competition for the binding sites on albumin. Physiological and pathological in· creases in bilirubin and free fatty acid plasma con· centrations are often encountered in the neonatal period.

ophyUine are useful for calculation of dose. Rear· ranging the following equation (Wagner et aI., 1965),

(Eq.3) for a drug with complete bioavailability (F "" 1), the dose (0) for a desired steady state plasma con· centration (Css ) can be calculated according to Dose -

4. BTOllchodiiators 4.1 Theophylline Renewed interest in the clinical use (Simons et aI., 197 5; Weinberger and Bronsky, 1974; Uauy et aI., 1975) and disposition (Ellis et aI., 1975; Levy and Koysooko, 1975; Levy et aI. , 1974; Wellin et aI., 1975 ; Levy, 1974) of theophy lline in children has emerged. An understanding of bioavailability, plasma level-effect proftle, and elimination of the·

Css • Kelsl' .

Vd • W •t

(Eq.4)

where dose is given as mg per dosing interval (I) and 'w' is weight in kg. The discussion to follow will emphasise calculation of pharmacokinetic par· ameters as a determinant of dose. Unpredictable absorption of theophylline after rectal administration (Wrner and Shack, 1950) may cause accumulation with toxicity after mul· tiple doses. The intravenous route is preferred for absolute bioavailability, although solutions and tablel preparations are well absorbed after oral ad· ministration (Levy, 1974; Welling et al., \975).

Oinicel Phlfm&COkinelics in Infants and

7

Child~n

The therapeutic plasma concentration-time course profile of theophylline is apparently determined by linear kine tics (Levy, 1974; Weinberger and Bronsky, 1974). The elimination of theo phyl. line by children shows important differences as compared with that of adults (table II). The study by Ellis et al ( 1975) is one of the few to make such a comparison with common design and methods. For children, the clearance of theophylline varied 7-fo ld between individuals, whereas the volume of distribution varied 2-fold. A similar pat· tern of variation emerged for adults excep t that the clearance, as compared with that of children, was much lower (a mean of 87 vs. 57ml/h/kg). Maturation-depe ndent changes in clearance result in an increase in the weight·adjusted dose and probably ex plain the use of high doses and the wide variation in recommended doses for children found in the literature (Hyde and Floro, 1974; Johnson et al., 1975). Recen t clinical studies (vide infra) undeI1lcore the utility of more precise dose estimates. In asth· matic children an improvement of forced expira. tory volume in the first second (FEV I) was related to the log concentration of theophylline in tissue and the amount of the drug in plasma. Although a high initial peak plasma level followed bolus injection by iv route, the respiratory function improvement did not reach a maximum until a tissue/ plasma equilibrium was observed. Thus , peak. effect was seen about 30 minutes after bolus injection. During the post-distributive phase the effect was correlated with Ihe plasma level (or log of the concentration). Similar pharmacodynamic observations have been made for adults and child ren , such that an appropriate therapeutic plasma level range fo r theophylline is 10 to 20pg/ml (Jackson et aI., 1964; Mitenko and Ogilvie, 1973; Nicholson and Chick, 1973; MaseUi et ai. , 1970; Levy and Koysooko, 1975; Jenne et al., 1972; Weinberger and Bronsky, 1974 and Levy et aI., 1974). A somewhat similar range (5.4 to 241Jg/ml) was found when levels in saliva of asthmatic children were compared with those in plasma by USing a plasmal

saliva proportionality factor of 1.734 (Levy et al., 1974). Such a factor would be pred icted since at therapeutic concentrations theophylline is bound 55 to 63% to plasma proteins. This relat ionship is quite constant on repetitive estimation over several weeks in the same ind ividual (Koysooko et aI. , 1974). Use of saliva samples will facilitate estimates of the Css(avg)t (average steady state during a dosage interval [t])

Aue

(Eq. 5)

Css tavgh :: - ,-

where AUe is area under the curve detennined with 4 t o 6 samples during the dosing interval (t). Saliva concentration measurements of theophylline may prove useful in apnoea of prematurity, which has recently been shown to respond to theophylline (Uauy et aI., 1975). The dose and

Table III. estimated theophylline levels in pl;nma as a function of elimination rate l

Plasma conce nl ralion (/-Ig/ml) estimated3 at time th) alter dosing

0.2 0.3 0.4 0.' 0. •

0'

2

3

4

9.' 9.' 9.' 9.' 9.'

6.37 5.21 4.27 3.49

5.21

4.27 2.86 1.92 1.28 0.86

2.86

3.86 2.86 2.12 1.57

, • 3.49 2.12 1.28 0.78 0. 47

2.86 1.57 0.86 0.47 0.26

1 Kelp range ba!llld o n date of Ellis et al. (1975) for I~p

of 1.42-7.85 in children.

2 Celculated: DoseIVd ' Assume 4mg/kg/dose, 6·vear· old child, wt· 24kg and V d • 0 .422l /kg Co" 96mg!10.11- 9.5Omgl/ 3 eUimated plasma level decline eccOf"ding to C - Coe- kt for eech K.lp at eech time It) alter a lingle dose (Levy et al. 1975 duaibed C" 5 .54 e- 5 . 7 1t + 1.10 ,-0.23 11)

•

Clinieel Ph",n"*X)kinetia in Inf."u end Childrlfl

T,b/, IV. PitfaU, in theophvlline dosing .. a function 01 differences in clearance

~")

h"

L~

0.2

V, ml/kg

422

clt.... nee

High clearance

V,I

ml/kg/h

""" ""

. ... . 96

240

0 .•

422

253

240 480

96

IntefVlI h

•• • •• • 2

EnifTlllted plMfTIII leYel

Oh ""ml

2h ""ml

9 .• 23.7 47.4

6.37 15.88 31.77

9 .• 23.7 47.4 9.5

2.86 7.13 14.27 12.36

4h ""ml

6h ""ml

8h ,.gIml

'86

7.13 14.27

0.26 0.65

1.29

13.22

13.48

13.56

for multiple dosing.

duration (4mgJkg/day for 6 days) of theophylline used in these infants and observance of few side· eHects suggests that clearance of the drug was not significantly impaired , but no pharmacokinetic data are available on this question. Reliance on plasma (or saliva) level data as a strict guide for dosing of theophyUine can be misleading. Many clinicians now measure the level in plasma just prior to a subsequent dose when the drug is being given 6-hourly. Arter a single bolus injection, a wide spectrum of levels within I to 6 hours after a dose could be predicted as a funct ion of interindividual variation in elimination (~~) (table III). When low plasma levels are detected at the end of the dose interval , the dose of theophyl· line is often increased. The consequenct$ of an increase in dose are apparent (table IV). Initial (CO) levels could be toxic whereas the 6 hour level remains sub-therapeutic, i.e. with high clearance (short half.life) wide swings in the plasma level can occur. As an alternative, conside r using the same dose (e.g. 96mg) at more frequent (2-hourly) dosing intervals such that an acceptable plasma level is found at 2 hours and at 8 hours arter the

initial dose. In practice this pitfall of high initial levels with an increase in dose could be detected by measurement of 2 and 6 hour levels andlor Cs.s(avg)t. As indicated by levy (l974), a sustained release preparation may be appropriate for treatment of outpatients who demonstrate high plasma clearance of theophylline.

5. Cardiac Glycosides

5.1 Digoxin Of the cardiac glycosides only digoxin will be considered here since it is virtually the only glyco· side used in infants and child ren . In adult patients with cardiac disease, 70 to 90% of an iv dose is recovered as unchanged drug in the urine (Doherty and Perkins. 1962). The disposition of the drug in plasma is characterised by a biexponential decay, the half-life of the slow (tI) phase varying between 10 and 55 hours (Doherty and Perkins, 1962). Even greater variation has been reported in the literature .

9

Treatment of infants and children with digoxin is complicated by the age..clependent dose require· ment. A compilation of the dose recommendations for various ages by some authors is given in table V. A general agreement seems to exist on the fact thai infants between I month and 2 yean of age require higher weight·adjusted doses than both neonates and older children. These different dose recommendations are reflected by the fmdings by various authors (Dungan et aI., 1972 ; Morselli et aI., 1975) that the half·life of digoxin is shorter in children of the I month to 2 years age group than in younger or older subjects. Similarly, the latter authors compared the plasma clearances between different age groups and found differences that are consistent with the variation in dose recommenda· tions and half·lives. Their data are summarised in table VI. Infants and children of various ages achieve the same 'mean plateau' serum concentration of digoxin (measured 5 to 7 hours after an oral dose) despite a weight·adjusted dosage which decreases

with age according to Krasula et al. (1972) in table V. Possible explanations for this include lower absorption in the younger age groups, or decreasing metabolic o r renal clearance with age. However, the same authors also measured the post·absorptive serum concentrations which in all groups were proportional to the given dose. This indicates that absorption was similar in the various groups, although measurement of the area under the plasma concentration time curve after paren· teral and peroral administration would have been more appropriate to determine the bioavailabUity. More extensive tissue binding in infants and children compared with adults offers an alternative explanation for the lower plasma concentration· dose ratios in infants and child ren. This hypothesis has received recent support from a study by Goro· discher et al. (1975b). They found that the myo· cardium-serum digoxin concentration ratio was twice as high in infants compared with aduhs. Also, the ratio between digoxin concentrations in erythrocytes and plasma was about 3 times higher

T~tI V. Dailv dOleS (micrograms per kg body weight) of digoxin recommended lor perote' maintenance ther8PV in inf.nu Ind children 01 various . .

Prema-

Months

'""

0 1 2 3 4 l G- 12.5

• •

Years

• •

•• • •

• •

4.5-7.5 3 7.5-12.5

•• ••

1 2 3 4

15-20

20-2.

15-20 16-20

Reference

20

.... ••

.....

••

7 8

....adul1li2

10-15

I.

••

9 10 11 12131415 iii

9

•

•

Neill (1965)1 Goldblatt (1962) Kresule el a!. (1972)

10-15

Shirkey (1973b)

10-15

NellOn's Text· book of Pediatric. (1975)

1 Maintenance dose assumed to be )(, 01 the total digital ising dose. 2 Maintenance dose in adu lu 3.6-10.7 t.Md on 70kg body weight (Goodmln and Gilman, 197513 IV 01' 1M melntenance dote MaImed to be 151100 01 the total digital ising doH.

'0

r.bI. VI Me.n .... Iues of helf-lives !Iii)' plasme c l.. nmce lap!. IIPP.r.nt YOlumII 01 distribution IVd) 101' intravenously adminlst.red digolllin In dill.renl. ~OUPI of children (Monelli et al., 1975)

Iii (hour,)

3-' ...,.

1.3-11 monthl

vean

6'

18

37

2-'

Cl p lml/min/kg)

1.8

10.7

~.

Vd Ulkgl

7.'

'~3

16.1

11 .1

22.8

17.3

Dole tug/kg)

in the infan ts compared with adults. These results could not be explained on the basis of different plasma protein binding. The different distribution and evidently greater Vd in infants (also noted by MorselJi et aI., 1975), may partly explain the higher digoxin dose requirements in this age group. The apparent V d of digoxin has been measured in infants and children of various ages (Morselli et aI., 1975). They found that the Vd increased 2-fold from one group (3 to 9 days) to another group (I.3 to II months) of infants. Howeve r, the t~ and Kel in plasma, importa nt de terminants of the steady state concentration, changed 3 to 4·fold between the same ages. The above-mentioned findings indicate that the renal (and/or metabolic) clearance has greater importance than the apparent Vd fo r the age dependent variation in the plasma clearance of digoxin. The reason fo r the 6-fold increase of digoxin clearance between the first two age-groups of table V1 is not known. Increased metabolic clearance is not plausible in view of the fact that less than 10% of digoxin is metabolised in adults (Doherty et ai., 197 1). In infants between 6 days and 5~ months, Hernandez et aI. (I969) did not find any metabolites of digoxin in urine. Increased renal digoxin excretion offers an alternative explanation, previously proposed by Soyka (I972). The available published data are

conflicting on this point. Thus, (jsalo et aI. (1974) with the use of radioimmunoassay technique calculated that about 47% of a daily digoxin dose is excreted in urine per day in infants and children between 12 days and 7 years. This is less than in adults. The authors assumed that their digoxin elixir was 100% absorbed. Interestingly, they arrived at similar values fo r the renal digoxin clearance as did Gorodischer et aI. (I975a) in a later report. The latter authors also related their data 10 creatinine clearance and showed tha t the renal clearance or digoxin in I to 5 months old inrants with congenital heart disease was twice as high as that of creatinine at any given age. In adult patients renal digoxin clearance equals that or creatinine. These data are consisten t with the higher digoxin doses required in inrants and children although they only orfer a partial explanation. The same authors also suggested , o n the basis or pharmacokinetic analysis, that the kidneys must be quantitatively the most important route or elimination , as would be expected rrom adult data. Another recent report (Wettrell et aI., 1974) is partly con mcting with the above-mentioned findings. Thus, these authors did not lind a difference between digoxin and creatinine clearance in newborns and inrants of similar ages. They collected urine in 24 hour periods and assayed it ror digoxin with two methods which gave similar results. The reason ror the conmcting results cannot be elucidated rrom the published papers. In both reports though , there was a significa nt correlation be tween age and the renal clearance or digoxin. Whether the intrinsic activity of digoxin is dirferent in the human inrant and adult myocardium is not known. Dale on the pharmacodynamic erfects or cardiac glycosides in infants and children of various ages do not see m to be available. In infants and children, the se rum conce ntration correlates closely to the myocardial concentration (Gorodischer et a\., 1975b). Some da ta (Wettrell et al., 1974) indicate that infants may be without side~frects at serum digoxin concentrations

11

Oinic.. Ph.. rNCOki ..... ti(:s in Infann and Children

usually considered as toxic in aduils. In rabbits, recent findings (Boerth, 1975) indicate an increa· sing sensitivity with age to the positive inotropic effects of ouabain. The available literature on the digoxin kinetics in newborns, infants and children does not point to a specific causative factor for the different digoxin requirements in these age-groups. Distri· bution factors as well as changes in the drug elimi· nation capacities all seem to playa role, perhaps with different relative importance during each of the maturational periods.

6. Anrihypenensh'e Drugs

6.1 Diazoxide Diazoxide is being widely used in children for trea tment of hypertension and hypogiycaemia. Its biological fate was recently studied in man (Pruitt et aI., 1973; Pruitt and Foroy, 1975). A Vd of O.331/ kg and a t-n of 24 hours with 33% ofa dose excreted as unchanged drug in the urine per day was found in a 6. lkg child after iv administration of a 60mg bolus dose. A maintenance dose of 6.5mgfkg for 3 days was associated with a plasma level of 50J..lg/m1. This patient was later intoxicated (I20J..lg/m1) and the plasma elimination proceeded by apparent zero-orde r kinetics. The concentration in cerebrospinal nuid was 17.8J..1g/m1 at a plasma level of 120J..lg/ml, which is consistent with the plasma protein binding in man of 90 to 93%. Chronic treatment with diazoxide (6mg/kg/ day) in an additional child with a weight of 17kg was associated with a tih of 9.5 hows after the drug was withheld. Another child showed a t~ of 19 hours after chronic treatment with diazoxide (7mg/kg/d.y). After an oral dose (300mg) in two adults, half· lives of 24 and 36 houn were found. It is of interest that the child with the shortest t-n had been receiving phenobarbitone, phenytoin

and primidone. One child treated with phenobarbi. tone, had a diazoxide plasma t~ of 24 hours before and 21 hours after treatment. Additional studies in infants less than 6 months of age reo veaJed a t-n of 20 to 40 hours which showed a direct relationship to age. A similar pattern for an age·dependent increase in t~ was shown for dog! (Pruitt and Foroy, 1975). Data from this and other studies (Sellers and Koch·Weser, 1969 ; Symochowicz et aJ., 1967) in adults suggest that plasma elimination rate in the child is greater than in the adult. Therapeutic indications probably require dis· parate plasma concentrations with a range of 15 to 50J..lg/mi being appropriate for treatment of hypo· glycaemia (Pruitt et a1., 1973), whereas a level (acutely) of 300 to 400J..lg/ml may be necessary for relief of hypertension (SeUers and Koch·Weser, \969). 6.2 Propranolol 1ltis drug is being used in children for a variety of disorders, including hypertension. An early study of 4 children in comparison with adulu revealed a wide variation in plasma levels (Shand et a1., 1970). Wilson et aJ. (I975a) reported on the bioavailability of two formulations (liquid and tablet) of propranolol in 7 additional child ren . Formulation differences were not detected with regard to variation of concent ration of propranolol in plasma. For one patient, area under the plasma level time curve measurements were similar after either fo rmulation. The most striking finding was a lack of a weight adjusted dose·plasma level rela· tionship for this population of children. When comparisons were made of the plasma level just before a subsequent dose, marked interindividual variation in either the plasma level or the dose was found (Wilson et aI., 1975a). These findings are a consequence of the 'first·pass effect' since pro· pranolol undergoes extensive extraction as it passes through the liver following oral administra-

OlniceJ Ph ... rnecokinetia in Inf."b end Childr.n

tion. The fraction available (F) is thus limited by the amount of that extracted (E) where (Eq_ 6) and the value of E in a given patient is determined by E _ AUC;. - AUc". AUC;.

(Eq.1)

Varialion in E, rather than t~ probably ac· coun lS for the differences in plasma levels of propranolol for children (Wilson et aI., 1975a) as has been described for adults (Shand et aI., 1970). Thus, for this drug the recommended dose is only a guide and the exact bioavailability must be ascertained by plasma level analysis in each child.

7. Antimicrobial Drugs 7.1 Sulphonamides

12

Dicloxacillin renal clearance was aboul 3·fold that of adult controls. Creatinine but not urea clearance was increased_ The increased renal clearance in the cystic fibrosis patients could not be attributed to the slight difference in serum prolein binding. In the above study age was not identified as a major determinant of the observed differences in dicloxacillin pharmacokinetics, but children less than 9 years old were not studied. In the report of Jusko el al. (1975) the following equations were used to describe data consistent with a change in both the renal (CIR) and metabolic (CIM) clearance of dicloxacillin in patients with cystic fibrosis (assume fraction available (f) does not change in either group I : AUC -

7.2 Penicillins

7.2.1 Dicloxacillin Practical consequences of dicloxacillin kinetics have been described for children with cystic fibro· sis as compared with normal aduhs (Jusko et al., 1975). In both groups of subjects an o ral dose of dicl oxacillin was rapidly eliminated (hh 1.2 to 1.4 hours) after a peak serum level at I hour. Bioavailability (measured as fractional amount excreled in urine) was similar but serum concentration and area under the concentration versus time curve (AUe) was lower for the cystic fibrosis subjects, despite similar plasma prolein binding, 88.4 and 94.4% in the patients and normals, respectively.

a.

(Eq. 8)

where 0a • OA + CIM' If

The disposition of a long-acting sulphonamide has been studied in children by Sereni et al. (1968). The reader is referred to their paper for the numerous pharmacokinetic considerations, when this type of drug is appropriate for use in young patients.

F· Dose

ClasJ · CIA.

(Eq.9)

where J is a proportionality factor, then , equation 8 can be arranged to:

-

Do" -AUC

J

-

F

. CIA

(Eq.IO)

(y - b ' xl

A plot of dose/ AUC versus CI R gave a slope (J /F) of 1.92 which, when corrected for F '" 0.8 (bioavailability) gave J :: 1.54. Multiplication of a normal CIR (95mJ /min/ l.73ml) by J gave total body clearance (CiS :: 146ml/min/ l.73m 1 ) such that C1M :: C1e-C IR :: 5 J ml/ min/ I .73m 1 in agreement with that found for normal subjects. On the other hand, if a constant metabolic clearance were operative, then, by rearrangement of equation 8. we have : Dose

-AUC

- -OA

F (y-bx+a)

(Eq. II)

Oinical Ph.mac:okinelics in Infants and Children

The data wouJd be expected to describe a situ· ation whe rein both metabolic and renal clearance would not increase in similar proportion. The data for children with cystic fibrosis did not fit this latter situat ion. Jusko et al. (1975) concluded that little observed change in t~ in normal versus cystic fibrosis patients was a result of similar tissuel plasma distribution rates in view of rapid renal clearance. Oearance, therefore, rather than half· life more accura tely reflected elimination of dicloxa· cillin. It was proposed that an enhanced renal tubular secre tion was responsible for the increased renal clearance of dicloxacillin (and creatinine) found in children with cystic fibrosis. On the basis of these findings a 2·fold dose increase of dicloxa· cillin was suggested as being appropriate for cystic fibrosis patients.

7.3 Tetracycline Use of tetracycline in the young child must be weighed carefully because of effects on teeth and bone (cf. Wilson, 1972). Sereni et al. (1965) have described the dispoSition of a tetracycline, Iyme. cycline (tetracycline·l·mcthylene-Iysine), in newborns and 2 to II month old infants. After an oral or im dose , the plasma level was sustained higher in the newborns after 6 hours. Variability in levels at each time period was minimised by im dosing. Clearance of the drug (and creatinine) was lower in newborns compared with that of infants and child · ren 3, 4 and 9 years old. In general, after iv dosing the plasma clearance for this tetracycline showed a direct increase with age (from I day to II years). An age-dependent increase in Vd was noted during this time with a 3-fold increase seen between 7 months and 5 years. The reduced clearance (probably secondary to decreased glomerular filtration) of the tetracycline in newborns and older infants indicated that , if the drug must be used , the dose should be reduced accord· ingly.

13

7.4 Erythromycin The pharmacology, disposition and clinical use of erythromycin has been reviewed recently by Seu and Wilson (1974). 7.5 Clindamycin C1indamycin, a derivative of lincomycin, has been studied in children between 2 months and I I years of age (Kauffman et aI., 1972). The drug was given im as the phosphate ester, which is inactive per se, but bioactivated by hyd rolYSiS. With the use of a b ioassay method, the authors measured serum clindamycin 'activity' which may be derived from bot h clindamycin base and other met· abolites. Two doses were given,either 117 or 150mg per square metre. Peak serum concentration was observed in both cases within I pour, which is considerably earlier than tha t observed in adults. Clindamycin activity exhibited dose-dependent elimination kinetics. The mean half-life was 2.4 hours after the lower dose and 3.4 hours after the higher dose, indicating saturation of a rate-limiting step in the elimination process with therapeutic doses. However, both values were Significantly below 4.5 hours, which has been reported for the rate of elimination of antibiotic activity in serum of adults, given a dose of 173mg per square metre body surface im (Novak et aI., 1970). This was in part ascribed to a greater urinary excretion of the antibiotic. The results indicated a more rapid absorption with higher peak levels (about 2-fold) of c1indamycin activity in the infants and children compared with adults. Microbiological assays showed that adequate serum antibiotic activity against Gram-positive bacteria during the entire dosage interval was achieved only with 150mg ctindamycin phosphate per square metre. lltis single dose was well tolerated by all patients.

'4

Oinieal Ph.,m.lOkineties in Inh",ts end Childrllfl

T.bI. VII Kinetics of phenobarbitone in inf.nts.nd children

ve.rs:months

Plasma half·life (r.nge in houri)

GilrrettlOn.nd Deyton. 1970

0 : 10-4 :0

37-73

Jailing. 1974

0 :9- 2 :7

37- 133

Ago

8. Anriconllulsant Drugs

8.1 Phenobarbitone The main use of this drug in children is in epilepsy and febrile seizures, but it is also used experimentally in the treatment of congenital nonhaemolytic jaundice (Yaffe et aI., 1966). Despite its use for a ol ng time very little is known about the kinetics in children of the ages within the scope of this article. As is the case with phenytoin, children below the weight of 30kg were found to require higher doses of phenobarbitone than adults (per kg body weight) to achieve the same plasma steady state concentrations (Svensmark and BuchthaJ, 1964). These fIndings are in accordance with the dose recommendations for phenobarbitone in various textbooks and dosage handbooks (Nelson et ai. , 1975; Shirkey, 1973; Goodman and Gilman, 1975) where about 2·fold higher doses are recommended in infants and children as in adults. Svensmark and Buchthal (1964) postulated that this was due to fast elimination of the drug and evidence for this has appeared in the literature (vide infra). Garrettson and Dayton (1970) studied the plasma half-life of phenobarbitone in 6 children between 10 months and 4 years of age. Four of them had been accidentally poisoned and their half·Jives varied between 37 and 64 hows. Two children received parenteral treatment and had half·lives of 38 and 73 houn. Table VII compa res the reported half-lives of phenobarbitone in child-

Elimi,...tion rete co,..tent (hours-I)

Volume of dimil;Ju· tion If per kg)

0.0052- 0.0188

0.47- 0 .78

ren with those observed in infants between the ages of 9 months and 2~ years (Jailing , 1974). No other data have been published in the literature on phenobarbitone half-lives in older infants and children given this drug on clear therapeutic indications. These values are in the same range as those reported in adults, namely 52 to 109 hours (Butler et a1., 1954) and 80 to 120 hours (lous, 1954). 1hls does not necessarily indicate a faster rate of metabolism, sin ce 10 to 25% of phenobarbitonc is excreted in the urinc in unchangcd form (Goodman and Gilman, 1975). However, one must con· sider the fact that the relative size of the liver is greater in children of these ages than in adults. Dose-dependent kinetics of phenytoin is observed in infants and children (see below) and implies that the plasma steady state concentrations increase disproportionately to the increase in dose, due to saturation of the enzymes and prolongation of the half-life. Phenobarbitone also seems to have dose-dependcnt kinetics in children (Jailing, 1974), but this depe ndency exhibits another cor· relation pattern since the elimination rate was positively correlated with dose and/or peak plasma concentration. TIlere is no explanation for this phenomenon. It may be postulated that the drug stimulates its own metabolism after only one dose 50 that this effect is noted aJready during the elimination of this same dose. Such an explanation would be consistent with the strong inducing effects of phenobarbitone on the hepatic drug metabolising enzyme system in experimental animals (Conney, 1967) and the maximum

Olnical

~rnecokin.tics

in tnt.no.rn;! Children

inducing effect after about 3 days in animals (Wilson and Fouts, 1966). On the other hand, no correlation between inili31 plasma concentration and half-life of phenobarbitone was observed in the study by Garretlson and Dayton (1970). From the available literature data, phenobarbi· tone does not seem to saturate the drug me tabolising enzymes within the 'therapeutic' plasma concentration range. Not even in the high conce ntration range of 20 to lOO/-Ig/mi in intoxicated children (Garretlson and Dayton, 1970) was saluration kinetics evident. Non·linear kinetics have been described fo r one intoxicated infant with a maximum plasma concentration of 204/-1g/m1 (Wilson and Wilkinson, 1973) but phenobarbitone could have been formed from primidone during the early part of the elimination. The absorption of phenobarbitone from the gastro·intestin31 tract occurs slowly. Peak concen· trations of similar magnitude are generally achieved in infants within 4 hou rs after either oral or im dosing (Jalling, 1974). Thus the al tter route of administration does not see m to be of major advantage. A well-established therapeutic plasma concentration range has not been found for phenobarbi. tone in children. The optimum plasma concentration range in adults is 10 to 25pg/ml ( Buchthal and l.ennox·Buchthal. 1972). To our knowledge, only one prospective study on the plasma concen· tration-effect relationship in children has been published ( FaeTr, et al., 1972). They studied the preventive effe ct of phenoba rbitone on febrile convulsions. The recurrence rate in a 6 month lime period of the febrile convulsions was 4% when the serum concen tration was 16 to 30/-lg/ml as compared with 2 1% in children with levels of 8 to 1Spg/ml.

8.2 Phenytoin The value of plasma level monitoring of phenytoin became evident when the relation between

" plasma concentration and effect was described in adults many years ago (Buchthal et al., 1960). Since then, several more reports have shown that there is a correlation between plasma concentration and therapeutic efficacy, 10 to 20/-lg/ml plasma being an optimum concentration for seizure prophylaxis (Kutt and McDowell , 1968: Lund , 1974). Ev31uation of anticonvulsant effects of drugs in children is difficult . Therefore , reported data on therapeutic plasma levels in infants and children are found infrequently. In general, similar but wider ranges than in adults have been suggested; 5 to 20 (Borofsky et aI., 1972) and 12 to 25/-1g/m1 plasma (Norell et aI., 1975). The use of this drug is complicated by its dosedependen t kinetics which is present in chlldren (Canemon and Kim, 1970) as it is in adults (Remmer et 31., 1969; Arnold and Gerber, 1970). In essence, this means that the drug metabolising enzymes, which fo r most drugs ope rate under apparent first-orde r kinetics, may easi ly become saturated by phenytoin as its plasma concentration rises. In some patients this occurs even within the 'therapeutic' plasma el vel range. Once the enzymes are saturated, the rate of enzymic metabolism is independent of drug concentration . Accumulatio n will occur , since under such conditions, the plasma half-life increases and the steady state concentrations rise disproportionately to the increase in dose. These characteristics of phenytoin make the handling of the drug somewhat difficult, especially in infants and children , i n whom side-effects are difficult to detect and dose-dependent kinetics are operative (Rane, 1974; Rane e t aI., 1974 ; Wilson et 31., 1975b). As in the case with phenobarbitone, larger doses of phenytoin (per kg body weight) are required in children below 30kg body weight in order to achieve the same plasma concentrations as in adults (Svensmark and Buchthal , 1964). Thus, there is a ol wer plasma concentration-dose ratio which also can be obse rved in young infants (J31ling et ai, 1970). In them, plasma concentra-

Cliniall PtI.,lT'IeCOkinetia in InfWlts

~

Chlld ... n

tions of 10 to 20pg/ml are not achieved even when they are treated with twice as large a dose as in adults, based on kg body weight. No explanation for this is presently at hand. It is tempting though, to discuss the differences between infants and adults in their body composition and relative sizes of the organs (fig. I) as a possibk: reason. Such differences might be associated with extensive extravascular binding of phenytoin and thus a greater apparent volume of distribution. Faster metabolism of phenytoin in older infants is an· othe r possible reason for the lower steady state concen trations. These possibilities are difficull to evaluate in children for practical and ethical reasons. The risks in these ages either for inadequate plasma concentrations or accumulation or pheny. toin with toxicity must be considered in conjunc· tion with the clinical efficacy and the pharmaco· kinetic properties of the drug. Such parameten seem not to be available in children below 30kg, as referred to above. However, Garrellson and Jusko (1975) recently reported on apparent Michaelis· Menten constants computed from data obtained in vivo in overdosed children. They found that child· ren between 6 and II years tended to have lower Km·values than adults. Since this value indicates the drug concentration at which the rate is one· half the theoretical maximum rate of metabolism, one would assume a greater risk for enzyme satur· ation and drug accumulation. However, the same authors also presented evidence for a higher apparent firSl-order rate constant for fo rmation of the main metabolite, p-hydroxy-diphenylhydantoin and the theoretical plasma half·lives were shorter than in adults. Thus, the lower Km·values are balanced by shorter half·lives which would minimise the risk of development of toxic drug concen· trations. In a recent study, we have measured the plasma conce ntrations of p-hydroxy-diphenylhydantoin in children treated with this drug because of epilepsy (Wilson et al., 1975b). Most of them had a recent onset of the disease. Two dosage regimens were

,. employed ; either 4 loading doses of 6mg/kg every 8 hours followed by the same dose , given daily in 2 divided portions; or the same constant dose from the beginning (ordinary regimen). In the first group of children , 'therapeutic' (10 to 20pg/ml) plasma levels were reached within 16 to 38 hours without any side~ffects. Children who received constant doses from the start of therapy required 5 to 13 days to reach a level of 10pg/ml plasma. An unexpected high frequency of allergic side reactions occurred in both groups of children. The reason is unknown but is under current investi· gation. The kinetics of the main metabolite p-hydroxy-diphenylhydantoin was in many respects similar to that found in adults ( Hoppel et ai., 1976). Thus , a 3-fold interindividual variation was noted in the ratios between unconjugated as well as conjugated p-hydroxy-diphenylhydantoin and parent drug, even between patients with simi· lar parent drug concentrations in plasma. This is probably a reflection of varying metabolic (and/or excretory) capacities. In general, the ratios were lower when the parent drug concentration was higher. The metabolite appeared in plasma from the very beginning of therapy and rollowed in parallel with the concentrations of parent drug in most cases. The levels were 0.5 to 4.2 (unconjugated) or 6.7 to 49.9% (conjugated) of those of phenytoin. Upon discontinuance of therapy or with rapid fall of parent drug concentrat ions, the levels of the metabolite tended to remain stable for 12 to 24 hours. They then fell in parallel with the parent drug concentrations. Similarly, in some children we no ted that the phenytoin levels increased. whereas those of the metabolite remained stab le during chronic treatment. These perturbations of the metabolite-parent drug ratios probably renect the presence of saturation (Michaelis-Menten) kinetics. Perturbation of this ra tio was observed also in newborns of epileptic women treated with phenytoin during pregnancy. The plasma levels of this drug decreased after birth in the newborn whereas the concentration of the unconjugated

Clinic-' Ph.l'T*lOkinetiCi in Infents end Children

P'"hydroxy-diphenylhydantoin remained fairly stable for 2 to 3 days (Hoppel et aI., 1975). A pertinent question that arises is whether the observed low concentrations despite high doses (Svensmark and Buchthal , 1964; Jailing et aI., 1970) are adequate for seizure control in infants and young children. Only sparse data on the plasma concentration-effect relationship have been published (Borofsky et aI., 1972; Norell el aI., 1975). These authors did not group the patients according to age. It may be that infants do not need as high concentrations as adults. In this context it is also of interest that the plasma protein binding of phenytoin is lower in cord plasma and plasma from newborn infants than in adult plasma (Rane et aI., 1971 ; Fredholm et al., 1975); the unbound fraction being 68% higher in the infants. This tends to compensate , though nOI completely. for the lower total plasma concen· trations encountered in this age group. The plasma protein binding of this drug in older infants and chi ldren has not been reported.

8.3 Carbamazepine Carbamazepine was introduced as an anticonvulsant drug in 1962 and is preferentially used in grand mal and psychomotor epilepsy . The drug has gained great interest because of its transformation into an active metabolite, carbamazepine10,ll-epoxide, which has been identified in urine (Frigerio et aI., 1972) and plasma (Eichelbaum and Bertilsson, 1975) of patients treated with carbamazepine. In adult plasma, the levels of the 10,II-epoxide varies extensively (Eichelbaum et aI., 1975c), from 15 to 48% of the parent drug (MorseW, 1975). 20 to 30% of the daily dose of carbamazepine is recovered in the urine as carbamazepine-lO, I I-epoxide and the product of its further metabolism, trans-dihydro-dihydroxycarbamazepine (Faigle e t Ia., 1975). With t he use of a spectro photometric method, M, Uer and Rist Nielsen ( 1972) reported se ru m

17

concentrations of carbamazepine between 7 and 9jJg/ml after daily doses of 10 to 20mg{kg body weight in children. In contrast to consecutive investigations by others, these authors claimed that there was a correlation between dose per k3 body weight and serum concentration. Other investigators have been unable to fUld a correlation between dose and steady state plasma levels both in adults (Meinardi, 1972; Christiansen and Dam, 1973) and children (MorseUi , 1975). Recent find ings have shown that carbamazepine induces its own metabolism (Eichelbaum et al., 1975a,b) which also may be induced by concom itant ly given drugs in adults (Christiansen and Dam, 1973) and children (Rane et al., 1975). In view of these fmdings it seems important to stratify patients with regard to length of therapy of carbamazepine and also with regard to concomitantly given drugs when one relates dose to steady state concentration. We recently studied the kinetics of carbam· azepine and its 10, II -epoxide in 43 epileptic children between the ages of I ~ and 15 years (Rane et al., 1976). All children had been treated with a constant dose of carbamazepine, and of o ther drugs in case of combinat ion therapy, for at least 4 weeks before the blood sample was drawn. In the whole group, there was no correlation between dose and steady state concentration of carbamazepine. However, by dividing the children into one group (A) with single treatment with carbamazepine and another group (B) with other drug treatment as well, we were ab le to see a weak correlation in group A but not in group B. This is in accordance with the lack of such a correlation in older children and teenagers on combined drug treatment (Morselli, 1975). Carbamazepine does not exhibit dose-dependent kinetics in adults (Levy et al., 1975) and neither did we find evidence for this in our study of children. The half- life of carbamazepine was measured in two children, I I (MP) and 10 (U ) years of age. MP had been treated for a non· epileptic disorder without any t herapeutic effect

18

~

~ao

I

u

j 6.0

2

8 !

!

I

azepine oxidation by the other drugs. It is assumed that the further metabolism and excretion, as well as the apparent volume of distribution of carbamazepine-IO. II -epoxide, is unaffected by combined drug treatment. A Significant correlation between plasma concentration of carbamaz.epine and its epoxide metabolite was found in both groups of patients,

4.0 2.0 1.0

t% .. 13.7

O.S

1%-18.9

o.

00.2

• I

12

24 36 48 60 Hou,.. .It .... last dose

72

a.-

•

10.0 96

9 .0

Fig. 3. Plum. hllf·Hle of earbemnepine, . . .ned in two children, 10 lUI end 11 IMPI VIII,. old. See teKI for

100 90

•8

•

8 .0

80

ea.. r,pon •.

whereas U developed a generalised allergic exan· thema on the 10th day of trealment and had to stop the treatment. As seen in figure 3, the half· life was 18.9 and 13.7 hours, respectively. These values arc lower than in adult patienls, either after single oral dose (mean 35.6 ± 15.3 hours) or after 15 to 20 days Irealment (20.9 ± 5.0 hOUri; Eichel· baum et al., 1975a), It is assumed Ihal carbam· azepinc induced its own metabolism in these children, sim ilar to that wttich occurs in adult patients (Eichelbaum et al. , 19753). At daily doses of 10 to 20mg/kg body weight the paediatric patien ts in our study achieved plasma concentrations similar to those in adults. This is shown in figure 4. Interestingly. a significantly lower (p< 0.01) steady state carbamaupine concentration was observed in the group of children on combined drug treatment when compared with the children on single treatment with carbamazepine. In contrast, the latter group of patients had a lower concent ration of carbamazepine-I 0, ll-epoxide when this was expressed as per cent of parent drug (p < 0.0 1). These differences probably reflect the induct ion of carbam·

7 .0

70

•

6 .0

8

00

-'-

••• ••

50 4 .0

~

••

'" 2 .0

.: N

~

u

1.0

C8Z A

8

50_ N

~

40 Q

8

-.--

.

•

E

60

u

I

_ 3 .0

• •

00

.

• •

00

1Expoxide

•

C8Z

!!!

I

-.. •

r

301

~

20 ::. 0

N

10

e

Epoxide

6

FIQ. 4. Steady IUlte plasma concentrations of carbe. mazepine (C eZ) and carbemazepin&-10. 11-epaxide IEpoxidel i" children either treeted oniv with cez (group A) or i" combination with o ther anttconvulsanu (group 81. Mean dl ily doleS _reI2.4 1 4.3 and 14.3 1 5.6mg in groups A and 8 f6q)8Ctively. Horizontall; nes ;"diclte the meal'll in each group.

'9

Oina! Ph.mec:okintties in Infants and Children

lhough slightly bener in Ihe single treatment group. This is probably due to the interindividual differences in the concomilant drug therapy , thus exhlbiling different degrees of inducing effects on the drug-metabolising enzymes. Altempts to relale the plasma concentration of carbamazepine to antiepileptic effect in adults have been unsuccessful (Eichelbaum et al.. 1975c). To some extent this might be due 10 Ihe aClive melabolite circulating in plasma. This is even more plausible in view of Ihe low plasma protein binding of the melabolite, about 50% as compared with 75% of lhe parent drug (Ioc. cit.). Therefore, it would be logical to measure plasma concentrations of both in future siudies on the relationship between plasma concentration and anticonvulsant effecl.

8.4 Ethosuximide The major indication for use of this drug is for absence seizures (petil ma l), a typical disease of childhood. II was introduced in 1958. Nevert he· less, it took several years until the first reports on the kinetics of this drug in children were pub· Jjshed. One early study was performed by Buchanan et al. (1969). Ethosuximide in singledoses of 500mg (as syrup or as capsule) was given 10 children between 7 and 9 years of age. The data were analysed according 10 a two-compartment pharmacokinetic model. Peak plasma concentrations were observed between 3 and 7 hours after the dose. The levels ranged from about 27 to about 51~ml wilh no significant difference between the capsule and the syrup form. The apparent volume of distribution was ca lculated to be 0.69//kg body weight. Interestingly the children's half-life of ethosuximide in plasma was lower than has been reported in adults; about 31 hours as compared with 60 hours, respectively. Similar half-Jjfe data were later produced by Chang et al. ( 1972) who found a mean half·Jjfe of 30

hours in children as compared with 66 hours in adulls. Short half·lives in the same range for children have also been observed by others (Sher ....in and Robb, 1972). These data can be used for calculating the steady state plasma concentrations during repeli. tive oral administralion. Assuming a mean daily dose of 3Orng/kg body weight (in 3 divided doses every 8 hours) equation 3 can be rearranged 10 give:

• 1.44·

tli .

F • Dose

Vd ' t

(Eq.12)

This gives an eSlimate of Ihe steady state plasma concentration (C ss). If complete absorption is assumed (Goodman and Gilman. 1975). tne calculated CS5 is about 80,LIg/ ml. This is a higher value than has been observed in 9 to 15.year-old epi. leplic children with continuous trealmenl wilh the drug (Van der Kleijn et al., 1973). In that study. plasma concentrations between 10 and 6O/-lg/ml were observed. One reason for the discrepancy may be Ihat the children were also treated with other antiepileptic and sedalive drugs, which might have induced the metabolism of elhosuximide and lowered the plasma steady stale concentrations. Somewhal higher plasma levels at similar doses were observed by Sherwin and Robb (1972). How· ever, these authors did not indicate how many of their patients were trealed also wilh other anti· epileptic or other drugs. Importanlly, there was a highly Significant correlation between dose and plasma concentration and the aU1hors also found a higher dose requirement in child ren than adults in order to acttieve a certain plasma concentration . This is consistent with the $horter half-lives observed for children. The last·mentioned invesligators also studied the steady state concentrations over longer time periods and found them to be very stable. Tllis is of great clinical value. The drug was found to be poorly bound to plasma proteins and in agreement with this, levels in cerebrospinal fluid equalled those in plasma.

20

OiniQlI Ph .. macokinetic:s in Inlanu and Children

In a study by Penry et al. (1972), maximum clinical control was obtained when plasma concentrations of ethosuximide varied between 40 and SOIJg/ml. 9. Analgesics

pranolol in this review. Intra-individual differences in plasma levels for drugs with high hepatic clear·

ance characteristics are thus determined by the extent of clearance of the drug from portal blood after oral administration. That this effect is oper· ative in children is clearly suggested by the data on propranolol and propoxyphene (Wilson et aI., 1975a).

9.1 Salicylates The dose-dependent nature of this drug as studied by Levy and his co·workers has been reo viewed recently (Wilson , 1975b) as it applies to dosing and occurrence of toxicity in children . 9.2 Propoxyphene Few potent, effective, non-narcotic analgesics are available for young children. As a prelude to erncacy testing in children, Wilson et aI. (1975a) studied dose requirements, i.e. bioavailability and plasma level·time profile, in 23 children given a single weight·adjusted oral dose of propoxyphene napsylate. Marked inter individual var iability ill plasma levels of both propoxyphene and nor· propoxyphene was found between I to 12 hours after the dose. For example, at 2 hours the variation was about 2a-fold for propoxyphene. Ethical and practical considerations limited half·life calcu· lations 10 two data points from each of 9 children. Nevertheless, the average t~ was 3.38 hours for the children and was not different as compared with that of adults.l A 4.7-fold range in I~ was found for the children and 3.I·fold for the adults, whereas an approximate 20-fold and la-fold re· spective variation in plasma levels was found. This kinetic behaviour is consisten t with a high frrst· pass hepatic elimination (Gibaldi et aI., 197 1) for propoxyphene similar 10 that discussed for pro3 Adult data 01 Wolen et al. (19711, Rodda et .t. (t9711 .nd Verbeley and Inturris;, C. E. (19741 tummarised by Wilson et .1. (197581.

Acknowledgements Part of our own studies in this review ....ere sup· ported by grants from the S",-edish Medical Research Council (B15-04X-4496-01; 3902-02B), the Assocbotion of the S""edish Pharmaceutical Indusll'y. the Karoiinsb Institute, Stockholm. S",-edcn and by grants from the NIH ( K4-HD425J9, GM-154Jl. GM·21949) and from Eli Lilly Company and Ayerst Laboratories. We thank lois P. Chu for her asslSlance In typing of the manuscript.

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