Gender, Pregnancy, and PKs
Contribution by Jules Levin, NATAP
Happily, mother-to-child transmission of HIV has become a rarity in the industrialized world. But a few million children are already infected elsewhere. As antiretroviral access continues to improve in those HIV epicenters, mapping out the PKs of antiretrovirals in children will assume even greater urgency.
The race is already on to fill the pharmacokinetic void left by surplus enrollment of men in most trials of current antiretrovirals. And for good reason, Francesca Aweeka observed: 58% of infected Africans are female, and 36% of infected Southeast Asians. Research already shows that saquinavir, nevirapine, lopinavir, and enfuvirtide (T-20) levels climb higher in women than in men, Aweeka said, while women attain lower quotients of efavirenz, AZT monophosphate, and AZT triphosphate. But weight, she added, can be a stronger correlate of antiretroviral exposure than gender. Pregnancy tends to taper exposure to saquinavir, indinavir, ritonavir, nelfinavir, and lopinavir.
A study published just before the Pharmacology Workshop detailed the effects of higher saquinavir levels among women than men also taking ritonavir or nelfinavir in a rescue regimen . Saquinavir concentrations proved higher with ritonavir than with nelfinavir. Women had higher saquinavir AUCs and higher Cmins than men did. And those higher levels made a virologic difference: 42% of women reached a viral load of 500 copies/mL or less by week 16, compared with 28% of men. Higher saquinavir AUC and Cmin raised the chance of getting the viral load under 500 copies/mL (P = 0.008).
4. Fletcher CV, Jiang H, Brundage RC, et al. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group study 359. J Infect Dis 2004;189:1176-1184.
FOLLOWING Reported by Jules Levin, NATAP
Sex-Based Differences in Saquinavir Pharmacology and Virologic Response in AIDS Clinical Trials Group Study 359
Courtney V. Fletcher, Dept of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver
AIDS Clinical Trials Group study 359 was a controlled study of saquinavir with either ritonavir or nelfinavir, together with delavirdine, adefovir, or both, in indinavir-experienced persons. Saquinavir was common in all study arms, and the study investigated relationships among characteristics of patients, saquinavir area under the curve (AUC) and trough concentrations (Cmin), and virologic response.
Concentrations of saquinavir were higher when it was combined with ritonavir than when it was combined with nelfinavir and were lower with adefovir-containing regimens.
Females had higher AUC and Cmin values than did males.
Higher saquinavir AUC and Cmin values were associated with a greater likelihood of human immunodeficiency virus (HIV) RNA levels ⩽500 copies/mL (P = .008) and were better predictors of response than was the saquinavir inhibitory quotient.
Males had a lower probability of having HIV RNA levels ⩽500 copies/mL at week 16 than did females (28% vs. 42%; adjusted odds ratio, 0.43).
In this study, a greater proportion of females had HIV RNA levels ⩽500 copies/mL than did males, which can be attributed to higher concentrations of saquinavir in females than in males.
The objective of the present study was to investigate relationships among concentrations of saquinavir, saquinavir inhibitory quotient (IQ), characteristics of patients, and virologic response.
Sex-based effect on concentrations of saquinavir, IQ, and HIV RNA responses. In the present study, females had statistically higher concentrations of saquinavir than did males. The median AUC value in females was 20.0 mg x h/L, compared with 14.9 mg xh/L in males (p=.0001).
The typical value of saquinavir clearance in females was 47% of that of males, after adjustment for body weight. At baseline, no significant difference in HIV RNA level or phenotypic susceptibility to saquinavir and indinavir was found between male and female patients. With respect to the 4 saquinavir IQ variables, females had higher IQ levels than males, with all except the IQFCAUC being significantly different.
Sex had a statistically significant effect on the week-16 HIV RNA response. Males had a lower probability of having an HIV RNA level ⩽500 copies/mL at week 16 than did females (60 [28%] of 216 males vs. 16 [42%] of 38 females). Multivariate logistic regression analysis found that sex was an independent predictor of the primary HIV RNA response, after adjustment for baseline HIV RNA level, baseline weight, and whether the regimen excluded delavirdine. The adjusted odds ratio between males and females at week 16 was 0.43 (P = .04; n = 247).
DISCUSSION By AUTHORS
We found that concentrations of saquinavir were a significant predictor of virologic response in an indinavir-experienced population. In the present study, concentrations of saquinavir were significantly higher when saquinavir was combined with ritonavir than when it was combined with nelfinavir and were lower in the presence of adefovir or adefovir plus delavirdine than in the presence of delavirdine. Higher saquinavir AUC and Cmin values were associated with a greater likelihood of achieving HIV RNA levels ⩽500 copies/mL at week 16, as well as a greater reduction in HIV RNA levels at weeks 4, 8, 12, or 16.
Females had significantly higher concentrations of saquinavir than did males, and, consistent with the relationship between exposure to saquinavir and virologic response, a greater proportion of females than males had HIV RNA values ⩽500 copies/mL at week 16. These new findings advance our knowledge of the clinical pharmacologic profile of saquinavir.
The observation that significant sex-based differences in virologic response can arise because of sex-based differences in pharmacokinetics also expands our understanding of the reasons why antiretroviral therapy may fail for patients.
Concentrations of saquinavir were significantly higher in females than in males. The clearance of saquinavir in females was approximately 50% of that in males, after adjustment for body weight. Females also had higher IQ values than did males. The sex-based differences in exposure to saquinavir were clinically significant--females were approximately twice as likely than males to achieve an HIV RNA level ⩽500 copies/mL at week 16. The manufacturer has reported that there was no sex-based difference in saquinavir (soft gelatin capsule) concentrations following a single-dose (1200 mg) study of 12 female and 18 healthy male volunteers . It is uncertain, however, whether the single-dose, non-steady-state design was suitable to discover sex-based differences for this agent, because of the processes that produce about 2-fold higher concentrations of saquinavir at steady state than after a single dose.
Saquinavir is a substrate for both cytochrome P450 (CYP) 3A4 and P-glycoprotein, and its low bioavailability is a result of the combined effects of limited absorption and intestinal and hepatic first-pass metabolism.
Sex-based differences in concentrations of other such substrates have been demonstrated. For example, an investigation of midazolam as a selective probe for intestinal CYP3A activity demonstrated a faster systemic and oral clearance in women not receiving oral contraceptives than in men. (21)
In contrast, the apparent oral clearance of verapamil, a mixed CYP3A and P-glycoprotein substrate (like saquinavir), was found to be slower in women than in men. (22,23)
These findings might indicate that the basis for the sex-based difference in concentrations of saquinavir arises as a consequence of expression or function of P-glycoprotein. Among other antiretroviral drugs, the oral clearance of nevirapine has been shown to be slower in women than in men. (24)
Interestingly, an analysis of data from bioequivalence studies submitted to the Food and Drug Administration demonstrated statistically significant sex-based differences in about 28% of the data sets. (25)
The extent of sex-based differences in pharmacologic characteristics of antiretroviral agents is not known, since these issues have received little rigorous study, and women often were underrepresented in the available studies. These data provide a compelling argument that trial designs with sufficient power to allow investigations of sex-based differences in pharmacokinetics and pharmacodynamics should be routinely employed in the development of antiretroviral drugs.
This investigation of concentrations of saquinavir, characteristics of patients, and virologic response has provided convincing evidence that sex is a statistically significant determinant of concentrations of saquinavir and that concentrations of saquinavir are a statistically and clinically significant determinant of virologic response.
As a consequence, males, as well as any patient who has low concentrations of saquinavir, are at an increased risk for virologic failure. The implications for these findings might be to administer a higher dose of saquinavir to males than to females.
However, concentrations of saquinavir are highly variable; in these participants, there was >400-fold variability in Cmin values. Thus, it is not certain that this strategy would provide sufficiently high concentrations to protect against failure for all males, and this strategy would do nothing for those females who have low concentrations.
Therapeutic-drug monitoring has been suggested as a strategy to improve the response and/or to minimize the toxicity associated with antiretroviral agents..
Two prospective studies have now demonstrated that concentration-guided dosing leads to a greater proportion of patients achieving undetectable levels of HIV RNA, compared with those who receive standard dose therapy (note from Jules Levin: TDM has limitations in its utility, interpretability, and application in clinical use but I think can be used in a limited individualized way certain special circumstances , and can be used in research situations examine weight, ethnic, hepatitis, and gender based differences in HIV drug levels. Its important to recognize the differences in opinion between researchers both in the USA and in Europe on the utility of TDM. Dr Fletcher has conducted a number of research clinical studies in this area and has strong opinions that TDM can be useful while other researchers have also examined TDM and found serious practical hurdles in using it in clinical settings in the US HIV care system as well as hurdles to its application and the interpretability of TDM results. You can read comprehensive TDM report discussing these concerns just posted in New Articles at www.natap.org).
The pharmacokinetic challenges illustrated by this investigation of highly variable concentrations among patients, sex-based differences in pharmacokinetics, and the dependence of virologic response on adequate concentrations are ones that could be addressed by a therapeutic-drug monitoring approach. It is acknowledged that antiretroviral therapy is already complex. However, therapeutic failure with antiretroviral regimens is still too common, and any therapeutic maneuver that might assist the clinician in improving the likelihood of response should be aggressively investigated to determine whether it plays a role in the treatment of patients.
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22. Kates RE, Keefe DL, Schwartz J, Harapat S, Kirsten EB, Harrison DC. Verapamil disposition kinetics in chronic atrial fibrillation. Clin Pharmacol Ther 1981; 30:44--51.
23. Krecic-Shepard ME, Barnas CR, Slimko J, Jones MP, Schwartz JB. Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol 2000; 40:219--30.
24. Zhou X-J, Sheiner LB, D'Aquila RT, et al. Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus--infected patients. Antimicrob Agents Chemother 1999; 43:121--8. First citation in article | PubMed 25. Chen ML, Lee SC, Ng MJ, Schuirmann DJ, Lesko LJ, Williams RL. Pharmacokinetic analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics. Clin Pharmacol Ther 2000; 68:510--21.