Journal of Clinical Pharmacy and Therapeutics (1992) 17,365-368

Variability in clinical pharmacology of drugs in children M. C . Nahata Colleges of Pharmacy and Medicine, The Ohio State University and Wexner Institute for Pediatric Research, Children's Hospital, Columbus, Ohio, U.S.A.

SUMMARY

Numerous factors can lead to variability in pharmacokinetics,pharmacodynamics,efficacy, and toxicity of drugs in infants and children. These may include age, race or genetic status, organ function, underlying disease(s), drug formulation, concomitant drugs, and compliance with therapy. Further research is needed to clarify the mechanisms for variability in drug response to achieve optimal use of drugs in paediatric patients.

INTRODUCTION

Progress in science and technology has led to increased understanding about the clinical pharmacology of drugs in children. A growing number of infants born prematurely are surviving, but often with conditions requiring continued drug therapy. Unfortunately, specific dosage guidelines are not available for the majority of marketed drugs for their optimal use in infants and children. Under such circumstances, it is important to consider potential sources of variability in drug response to maximize efficacy and minimize adverse effects in patients. The sources of Variability in clinical pharmacology may include differences in patient age, organ maturation, pharmacokinetics, pharmacodynamics, efficacy, toxicity, concomitant disease and drugs, race or genetic status, method of drug administration, dosage forms, stability and compatibility, and compliance with therapy. The purpose of this article is to discuss briefly the factors that may lead to the variability in clinical pharmacology of drugs in paediatric patients. Selected references will be cited to provide some examples. Correspondence:Dr Milap C. Nahata, College of Pharmacy, Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, U.S.A. Presentedattheannualmeetingof the Academy ofPharmaceutical Research and Science, American Pharmaceutical Association, San Diego, CA, 14 March, 1992.

It is well known that premature infants differ significantly from older children and adults due to physiological differences. Drug absorption from the oral route can be influenced by not only a higher pH, and slower gastric emptying but also from deficient pancreatic enzymes involved in the hydrolysis of drugs such as chloramphenicol palmitate. Intramuscular absorption of drugs in premature infants can be erratic; phenobarbital is absorbed well but diazepam is not. Percutaneous absorption of drugs (e.g. theophylline) may be increased, due in part, to lower thickness of the stratum comeum or increased skin hydration in premature infants (I). The extracelluar and intracellular fluid volumes as a percentage of body weight are higher in premature infants than in full-term infants, children and adults. This explains the highest apparent volume of distribution of drugs such as the aminoglycosides in these infants (2). Reduced protein binding can be important for highly bound drugs leading to increased free fraction. Decreased distribution volume of diazepam can be explained by reduced fat in infants (I). It is interesting that body composition can change significantly within the first week after birth. A decrease in the distribution volume of tobramycin within the first week can be explained in part by a decrease in extracellular fluid volume (3).Similarly, the clearance of drugs may increase due to maturation of liver or renal function with age. It is not possible to predict the degree of variability in clinical pharmacology of drugs due to partially developed liver or renal function. Some pathways are well developed even in neonates, e.g. metabolism of acetaminophen by sulphation, while others are not, e.g. glucuronidation of morphine, or oxidation of diazepam and theophylline. Theophylline clearance was substantially lower in infants up to 1 year old, compared with older children and adults (4).Interestingly, the clearance is highest in children 1-9 years of age; thus, they require a higher milligram dose per kilogram of body weight than adults or infants.

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The clearances of antipyrine, which undergoes oxidation, and lorazepam, which is conjugated in the liver, have been evaluated in two groups of children with acute lymphocytic leukaemia in remission, and a group of healthy adults. The clearance of antipyrine decreased with age when normalized for body weight but not when normalized for body surface area. The reverse is true for lorazepam clearance. This means that dosage may be based on body weight or surface area to achieve similar serum concentrations in three groups of patients studied (5). Note, however, that (i) substantial variability in clearance occurred within each of these groups; and, (ii) different isozymes within a major class, e.g. cytochrome p450, may be responsible for the metabolism of different drugs. Thus the direct extrapolation of these findings to all drugs may produce variable results. Drug eliminationby the kidney is reduced in premature infants due to decreased glomerular filtration and tubular secretion. The clearance of drugs, including aminoglycosides, and vancomycin increased with age (2,6).

It is not possible to determine the time after birth when the liver and kidney are fully developed. The data indicate that as much as 1 year may be needed. For example, chloramphenicol clearance has been shown to increase for up to 1 year of age (7). The time for full maturation can depend on the drug, enzyme system, and patient characteristics. PH ARM ACO K I N ETICS/ PHARMACODYNAMICS

Variability in pharmacokinetics can led to a modified drug response. Gilman et al. have shown that seizures occur in a patient due to incomplete absorption of carbamazepine (8).Treatment failure has occurred in a patient with osteomyelitis due to inadequate bactericidal titres, although the serum concentrations appeared adequate (9). Numerous studies have reported Variability in pharmacokinetics of drugs in infants and children. Chloramphenicol clearance varies by nearly lo-fold in children of different ages (7). Importantly, the bioavailability of chloramphenicol, after intravenous administration of chloramphenicol sodium succinate, has been found to be highest in premature infants, followed by infants from 1 to 12 months, and children above 1 year old. This is due to the lowest renal dearance of chloramphenicol succinate in premature infants,

leading to the highest fraction available for hydrolysis to active drug, i.e. chloramphenicol. Thus, the Gray baby syndrome may occur due to decreased metabolism as well as the increased bioavailability of chloramphenicol(10). Marked variability has been found in the pharmacokinetics of amphotericin B in children. Interestingly, the clearance decreased in patients between the ages of 1 and 10 years. Thus, it is tempting to speculate that some children may require lower than the currently recommended doses, and experience a lower incidence of adverse effects (1I). The pharmacokinetics of dopamine have been found to vary substantially in infants. Large interpatient variability has also been seen in the relationship between dopamine plasma concentration and mean blood pressure. However, this correlation was stronger in individual infants with escalating doses (12). The therapeutic dose of morphine required to control pain varies markedly in children with terminal malignancy. The plasma concentration varies nearly twofold between days of therapy in a patient receiving a set dose of morphine (13). Similarly, theophylline and rimantadine serum concentrations vary nearly fourfold in infants (4, 14). Adverse effects occurred in one infant who had the highest serum concentration of rimantadine (14). An attempt was made to construct a nomogram of vancomycin dosage requirements based on postconceptional age (15).However, this needs to be validated in patients. It has been suggested that theefficacy of erythromycin in patients with pertussis depends on the type of erythromycin. Many favour the use of erythromycin estolate over other erythromycins (e.g. ethylsuccinate or stearate in children), based on the fact that higher tissue levels can be achieved with the estolate form. Recurrence, however, can occur with any of the erythromycin, indicating that dosage regimen and compliance may also be important considerations in achieving efficacy (16). Renal toxicity occurs commonly in children receiving amphotericin B. However, cumulative doses and the elevation of serum creatinine do not correlate significantly (11).Similarly, no correlation has been found between the serum concentration of chloramphenicol and toxicity in children, although there is evidence of some relationship between cumulative dose and toxicity (17). The reasons for the variability in drug response are often unknown. For example, some patients with

Clinical pharmacology in children

bronchiolitis appear to respond to corticosteroids. Most infants with bronchopulmonary dysplasia respond to corticosteroids. Similarly, surfactants reduce mortality more significantly than the complications of bronchopulmonary dysplasia. We have recently found higher efficacy and lower adverse effects of sedation regimens (meperidine and/or diazepam) in children I I years old or more than in those less than 11 years old, who were undergoing gastrointestinal endoscopy (18). Concomitant drug(s) and disease(s) can modify drug response. For example, drugs inducing or lnhibiting hepatic enzymes, or those affecting renal excretion or reabsorption can affect the pharmacology of concomitant drugs. Phenobarbital can induce hepatic metabolism, cimetidine can inhibit hepatic metabolism, and probenecid can decrease renal elimination. The absorption of cefaclor in patients with short bowel syndrome is markedly reduced, perhaps due to a missing segment of intestine for absorption (19).Patients with cystic fibrosis require increased doses of many drugs including theophy Iline, aminoglycosides and penicillins, due to their increased metabolism and elimination (20). Phenytoin dosage requirements are often increased in patients with head trauma. This can be explained in part by increased clearance of drugs undergoing oxidative metabolism in the liver. The clearance of lorazepam, which undergoes conjugation, has also been found to be increased in these patients (21). O n the other hand, the dosage requirements of theophylline in some infants with bronchopulmonary dysplasia, and those of gentamicin in some paediatric patients with myelomeningocele may be lower than normal (22, 23). Dosage modification in children with renal dysfunction is usually made based on results in adults with renal disease. However, we have found that the pharmacokinetics of cefotaxime and its active metabolite may be different in children versus adults with renal dysfunction (24). Patients with human immune deficiency virus (HIV) infection may not respond to drugs or vaccines as well as those without this infection. The antibody response and protection from hepatitis B vaccine was lower in patients with HIV than those without (25).The toxicity of certain drugs, e.g. trimethoprim/sulphamethoxazole, is also increased in patients with AIDS than in those without. The severity of illness may affect pharmacokinetics and dosage requirements (12). Malnutrition can also decrease the clearance of drugs (26). Race and genetic status can explain a variability in drug response. For

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example, immunogenicity and the protective efficacy of a vaccine against Haernophilus influenzae type b is less than one-third among native Alaskans compared with a group of Caucasians in Finland (27). The method of drug administration can influence the pharmacokineticsand therapeutic response. Appropriate methods for medication preparation or reformulation, measurement of doses, and administration to patients should be utilized to achieve desired results. Intravenous drug delivery can depend on many factors including the type of device and tubing, method of infusion, flow rate, injection site, specificgravity of the drug and intravenous fluid (1).The stability and compatibility of commercially available reformulated or diluted drugs must be assured to minimize variability. The therapeutic monitoring of drugs should encompass the entire drug-use process (not just serum concentrations monitoring), to maximize the therapeutic benefits. Complete compliancewith drug therapy may often require ongoing education. We have found that counselling at the time of hospitalization or clinic visit alone may not assure full compliance with theophylline therapy in children with asthma (28).The theophylline serum concentration was subtherapeutic, ranging from 0 to 9.9 pg/ml in these patients at the time of repeated hospitalization and visits to the emergency department. Other factors, such as social or family background, and perceived efficacy or toxicity of drug therapy may play an important part in achieving compliance. In conclusion, the variability in clinical pharmacology of drugs occurs frequently in infants and children with different diseases. This can be minimized by an improved understanding of factors leading to the variability. The reasons for variability, however, are not well known in many cases. It is hoped that the advances in molecular biology will identify the mechanism for variability in drug response. We can make a substantial contribution through clinical pharmacy research, education and practice to achieve desired therapeutic outcomes in paediatric patients. REFERENCES

1. Nahata MC. (1992) Pediatrics. In: Pharmacobherapy: A Pathophysiologic Approach, pp. 56-63. 2nd edn, eds DiPiro JT,Talbert RL, Hayes PE, Yee GC, Posey LM. Elsevier, New York (in press). 2. Nahata MC, Powell DA, Durrell D, Miller M, Glazer J. (1984) Effect of gestational age and birth weight on tobramycin kinetics in newborn infants. Journal of Antimicrobial Chemotherapy, 14,59-65.

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3. Nahata MC, Powell DA, Durrell D, Miller M, Glazer J. (1984)Intrapatient variation in tobramycin kinetics in

low birth weight infants during first postnatal week. European Iournal of Clinical Pharmacology, 26,647449. 4. Franko TJ, Powell DA, Nahata MC. (1982)Pharmacolunetics of theophylline in infants with bronchiolitis. European Iournal of Clinical Pharmacology, 2.3,123-127. 5. Crom WR, Relling W ,Christensen ML, Rivera GK, Evans WE. (1991)Age-related differences in hepatic drug clearance in children: Studies with lorazepam and antipyring. Clinical Pharmacology and Therapeutics, 50, 132-140. 6. Lisby-Sutch S, Nahata MC. (1988)Dosage guidelines

for the use of vancomycin based on its pharmacokinetics in infants. European lournal of Clinical Pharmacology, 35, 637-642. 7. Nahata MC, Powell DA. (1981) Bioavailability and

clearance of chloramphenicol after intravenous chloramphenicol succinate. Clinical Pharmacology and Therapeutics, 30,368-372. 8. Gilman JT, Duchowny MS, Hershorin ER. (1988) Carbamazepine malabsorption: A case report. Pediatrics, 82,518-519. 9. Nahata MC, Jackson D, Powell D. (1990)Cefadroxil kinetics and dynamics in a pediatric patient with osteomyelitis. Chemotherapy, 36,392-395. 10. Nahata MC, Powell DA. (1983) Comparative bioavailability and pharmacokinetics of chloramphenicol after intravenous chloramphenicolsuccinatein premature infants and older patients. Developmental Pharmacology and Therapeutics, 6,23-32. 11. Benson J,Nahata MC. (1989)Amphotericin pharmasokinetics in children. Antimicrobial Agents and Chemotherapy, 33,1989-1993. 12. Bhatt-Mehta V, Nahata MC, McClead R, Menke J. (1991) Dopamine pharmacokinetics in critically ill newborn infants. European ]ournal of Clinical Pharmacology, 40, 593-597. 13. Nahata MC, Miser AW, Miser JS, Reuning RH. (1984) Analgesic plasma concentrations of morphine in children with terminal malignancy receiving a continuous subcutaneous infusion of morphine sulfate to control severe pain. Pain, 18,109-114. 14. Nahata MC, Brady M. (1986)Serum concentrations and safety of rimantadine in infants. European Journal of Clinical Pharmacology, 30,719-722. 15. Paap C, Nahata MC. (1990)Clinical pharmacokinetics of antibacterial drugs in neonates. Clinical Pharmacokinetics, 19.280-318.

16. Nahata MC. (1988)Selection of an erythromycin for the treatment of pertussis. h g Intelligence and Clinical Pharmacy, 22,895-898. 17. Nahata MC. (1989)Lack of predictability of adverse effects due to chloramphenicolin pediatric patients. Journal of Clinical Pharmacy and Therapeutics, 14,297-303. 18. Bahal N, Nahata MC, Murray R, et al. (1992)Comparative evaluation of sedation with four meperidine and diazepam dosage regimens in pediatric patients undergoing endoscopy. Pharmacotherapy, 11,43. 19. Nahata MC, Freimer N, Hilty MD. (1983)Decreased absorption of cefaclor in short bowel syndrome. Drug Intelligence and Clinical Pharmacy, 17,201-202. 20. Kerns GL, Reed MD. (1989)Clinical pharmacokinetics in infants and children: A reappraisal. Clinical Pharmacokinetics,17 (Suppl. I),29-67. 21. Boucher BA, Kuhl DA, Fabian TC, Robertson JT. (1991) Effect of neurotrauma on hepatic drug clearance. Clinical Pharmacology and Therapeutics, 50,487-497. 22. Nahata MC, Serafini D, Edwards R. (1989)Pharmacokinetics of theophylline in infants with bronchopulmonary dysplasia. lournal of Clinical Pharmacy and Therapeutics, 14,225229. 23. Nahata MC, McComb D, Schaad P. (1991)Serum concentrations of gentamicin in patients with myelomeningocele. Iournal of Clinical Pharmacy and Therapeutics,16,281-284. 24. Paap C, Nahata MC, Mentser M, Mahan J, Puri S, Hubbard J.(1991)Pharmacokineticsof cefotaxime and its active metabolite in children with renal insufficiency. Antimicrobial Agents and chemotherapy, 35,1879-1881. 25. Safasy A, Boscia J, Moonsammy G, Andre F. Anti HBs responses to hepatitis B vaccinationsin anti HIV negative and positive homosexual men and potential drug users. I n Interscience Congress of Antimicrobial Agents and Chemotherapy Abstract 188;1989. 26. Lares-Asseff I, Cravioto J, Santiago P, Perez-Ortiz 8. (1992)Pharmacokinetics of metronidazole in severely malnourished and nutritionally rehabilitated children. Chical Pharmacology and Therpeutics, 51,42-50. 27. Force R, Lug0 R, Nahata MC. (1992)hemophilus influeme type b conjugate vaccines. Annals of Pharmacotherapy (in press). 28. Nahata MC. (1991)Emergency department and hospital admissionsassociated with poor complianceof theophylline therapy, in children with asthma. Drug Investigation, 3,234-238.

Variability in clinical pharmacology of drugs in children.

Numerous factors can lead to variability in pharmacokinetics, pharmacodynamics, efficacy, and toxicity of drugs in infants and children. These may inc...
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