LETTERS TO THE EDITOR _ _ _ _ _ _ _ _ _ _ _ _ _ _~
C1in. Pharmacokinet. 21 (I): 81 -82, 199 1 0312-5963/91 /0007-0081 /$01.00/ 0 © Adis International Limited. All rights reserved. CPK1027A
Sex, Age and Alfentanil Pharmacokinetics It is very commendable that the report by Lemmens et al. (19: 416-422, 1990) includes pharmacokinetic data for the individual patients which is much more complete than is usually seen, While we agree with them that age is not influential for men, we disagree on their interpretation for women. Careful examination of the data presented suggests an alternative interpretation to the authors' conclusion that plasma clearance is age dependent in women. In their figure 2 the apparent decline with age can also be interpreted as a difference between women aged under and over 50 years (presumably pre- and post-menopause). In fact, neither of the regressions in these individual groups is significant (under 46, p = 0.28; over 55, p = 0.15) although both slopes are negative. The value of r2 (percentage variation in clearance rates explained) for the regression on age for all women (65.7%) is actually identical to the r2 explained by presumed menopausal status, and the p-value for the difference between the means of the 2 groups is nearly identical to that for the test of zero slope (p < 0.0001). This may be seen graphically in figure 1, in which the clearance rates are plotted against presumed meno-
pausal status. This figure should be compared with figure 2 of Lemmens et al. It would also be helpful to know if any of the female participants over 50 years of age were receiving estrogen therapy. Although premenarcheal women were not included in the study, data from other reports suggest the lack of gender influence on the clearance of alfentanil in neonates (Marlow et al. 1990) and that alfentanil clearance for children is similar to that found for adults (Meistelman et al. 1987; Sale et al. 1986). Important gender-related differences in drug metabolism are not generally observed in humans; when they occur, men commonly metabolise faster than women (Gibaldi 1991). Thus, we suggest another title for this interesting study: Hormonal Dependence of Alfentanil Pharmacokinetics in Women: Not Influenced by Age. We think this finding is original and should motivate other studies. ANA RUBIO
CHRISTOPHER Cox
University of Rochester New York
References 35 :2
30
2:
25 20 c: ~ 15 ~
«l
Q 10 5 O~~~~~--
< 46
________ Age
~
_______ > 55
Fig. 1. Plasma clearance of alfentanil in women by presumed menopausal status (data from Lemmens et al. 1990).
Gibaldi M. Bioipharmaceutics and clinical pharmacokinetics, 4th ed., pp. 252-253, Lea and Febiger, Philadelphia, 1991 Lemmens HJM, Burm AGL, Hennis PJ, Gladines MPPR, Bovill JG. Influence of age on the pharmacokinetics of alfentanil: gender dependence. Clinical Pharmacokinetics 19: 416-422, 1990 Marlow N, Weindling AM, Van Peer A, Heykants J. Alfentanil pharmacokinetics in preterm infants. Archives of Disease in Childhood 65: 349-351 , 1990 Meistelman C, Saint-Maurice C, Lepaul M, Levron JC, Loose JP, et al. A comparison of alfentanil pharmacokinetics and adults. Anesthesiology 66: 13-16, 1987 Sale JP, Goresky GV, Koren G, Strunin L. Pharmacokinetics of alfentanil in children. Anesthesia and Analgesia 65: SI-SI70, 1986
82
Clin. Pharmacokinet. 21 (1) 1991
The authors reply: We agree with Cox and Rubio that the difference in the plasma clearance of alfentanil between younger and older females could be related to hormonal changes, as we pointed out in the discussion section of our article. However, we disagree with their suggestion of changing the title of the study to 'Hormonal Dependence of Alfentanil Pharmacokinetics in Women'. This cannot be con-
cluded definitely from our study. Hormonal dependence must be proven in another study design. On the question about estrogen therapy in the elderly females, the answer is that none of these patients were receiving estrogens.
H.J.M.
LEMMENS
Protein Binding of Phenytoin In their timely article, 'Therapeutic Drug Monitoring of Anticonvulsants: State of the Art' (Choonara & Rane 1990), the authors present a review covering a large number of individual agents. While their advice and suggestions are well taken, I was disappointed to see no mention of the significance of phenytoin protein binding or the physiological role of the unbound portion of serum phenytoin. That patients with renal failure and/or hypoalbuminaemia have a modified range of therapeutic activity has been noted by others (Liponi et al. 1984). This important concept is often overlooked by practitioners adjusting phenytoin doses Drs Choonara and Rane have approved publication of the above letter and waived the right to reply. - Editor
in response to serum concentration values in patients with renal disease.
EARL L. MARBLE
Veterans Administration New York
References Choonara lA, Rane A. Therapeutic drug monitoring of anticonvulsants: state of the art. Clinical Pharmacokinetics 18: 318328, 1990 Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology 34: 395-397, 1984
C1in. Pharmacokinet. 21 (I): 81 -82, 199 1 0312-5963/91 /0007-0081 /$01.00/ 0 © Adis International Limited. All rights reserved. CPK1027A
Sex, Age and Alfentanil Pharmacokinetics It is very commendable that the report by Lemmens et al. (19: 416-422, 1990) includes pharmacokinetic data for the individual patients which is much more complete than is usually seen, While we agree with them that age is not influential for men, we disagree on their interpretation for women. Careful examination of the data presented suggests an alternative interpretation to the authors' conclusion that plasma clearance is age dependent in women. In their figure 2 the apparent decline with age can also be interpreted as a difference between women aged under and over 50 years (presumably pre- and post-menopause). In fact, neither of the regressions in these individual groups is significant (under 46, p = 0.28; over 55, p = 0.15) although both slopes are negative. The value of r2 (percentage variation in clearance rates explained) for the regression on age for all women (65.7%) is actually identical to the r2 explained by presumed menopausal status, and the p-value for the difference between the means of the 2 groups is nearly identical to that for the test of zero slope (p < 0.0001). This may be seen graphically in figure 1, in which the clearance rates are plotted against presumed meno-
pausal status. This figure should be compared with figure 2 of Lemmens et al. It would also be helpful to know if any of the female participants over 50 years of age were receiving estrogen therapy. Although premenarcheal women were not included in the study, data from other reports suggest the lack of gender influence on the clearance of alfentanil in neonates (Marlow et al. 1990) and that alfentanil clearance for children is similar to that found for adults (Meistelman et al. 1987; Sale et al. 1986). Important gender-related differences in drug metabolism are not generally observed in humans; when they occur, men commonly metabolise faster than women (Gibaldi 1991). Thus, we suggest another title for this interesting study: Hormonal Dependence of Alfentanil Pharmacokinetics in Women: Not Influenced by Age. We think this finding is original and should motivate other studies. ANA RUBIO
CHRISTOPHER Cox
University of Rochester New York
References 35 :2
30
2:
25 20 c: ~ 15 ~
«l
Q 10 5 O~~~~~--
< 46
________ Age
~
_______ > 55
Fig. 1. Plasma clearance of alfentanil in women by presumed menopausal status (data from Lemmens et al. 1990).
Gibaldi M. Bioipharmaceutics and clinical pharmacokinetics, 4th ed., pp. 252-253, Lea and Febiger, Philadelphia, 1991 Lemmens HJM, Burm AGL, Hennis PJ, Gladines MPPR, Bovill JG. Influence of age on the pharmacokinetics of alfentanil: gender dependence. Clinical Pharmacokinetics 19: 416-422, 1990 Marlow N, Weindling AM, Van Peer A, Heykants J. Alfentanil pharmacokinetics in preterm infants. Archives of Disease in Childhood 65: 349-351 , 1990 Meistelman C, Saint-Maurice C, Lepaul M, Levron JC, Loose JP, et al. A comparison of alfentanil pharmacokinetics and adults. Anesthesiology 66: 13-16, 1987 Sale JP, Goresky GV, Koren G, Strunin L. Pharmacokinetics of alfentanil in children. Anesthesia and Analgesia 65: SI-SI70, 1986
82
Clin. Pharmacokinet. 21 (1) 1991
The authors reply: We agree with Cox and Rubio that the difference in the plasma clearance of alfentanil between younger and older females could be related to hormonal changes, as we pointed out in the discussion section of our article. However, we disagree with their suggestion of changing the title of the study to 'Hormonal Dependence of Alfentanil Pharmacokinetics in Women'. This cannot be con-
cluded definitely from our study. Hormonal dependence must be proven in another study design. On the question about estrogen therapy in the elderly females, the answer is that none of these patients were receiving estrogens.
H.J.M.
LEMMENS
Protein Binding of Phenytoin In their timely article, 'Therapeutic Drug Monitoring of Anticonvulsants: State of the Art' (Choonara & Rane 1990), the authors present a review covering a large number of individual agents. While their advice and suggestions are well taken, I was disappointed to see no mention of the significance of phenytoin protein binding or the physiological role of the unbound portion of serum phenytoin. That patients with renal failure and/or hypoalbuminaemia have a modified range of therapeutic activity has been noted by others (Liponi et al. 1984). This important concept is often overlooked by practitioners adjusting phenytoin doses Drs Choonara and Rane have approved publication of the above letter and waived the right to reply. - Editor
in response to serum concentration values in patients with renal disease.
EARL L. MARBLE
Veterans Administration New York
References Choonara lA, Rane A. Therapeutic drug monitoring of anticonvulsants: state of the art. Clinical Pharmacokinetics 18: 318328, 1990 Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology 34: 395-397, 1984
