Background:  Aging can have a variety of influences on human pharmacology, largely mediated by changes in renal and hepatic function. The clearance of some drugs may decrease with advancing age, especially in patients classified as “very old” (age >80 years old). For metabolized drugs, this effect is most pronounced for cytochrome P450 (CYP) substrates.

Methods:  In one example, we hypothesized an age effect on the clearance rate of lopinavir (LPV), a CYP3A4 substrate. In the AIDS Clinical Trials Group (ACTG) 5015 protocol, HIV-infected subjects 18 to 30 (group A) or ≥45 (group B) years of age were enrolled in a prospective trial to examine age effects on immune reconstitution. All subjects received lopinavir/ritonavir (RTV) 400 mg/100 mg twice daily, emtricitabine 200 mg once daily, and stavudine 40 mg twice daily (weight ≥60 kg) or 30 mg twice daily (weight <60 kg). Single LPV and RTV concentrations were measured at 24, 36, and 96 weeks. Subjects periodically answered a questionnaire that asked the number of missed LPV/RTV doses in the previous 4 days, the within-subject means of which were compared with a Wilcoxon Rank-Sum test.

Results:  In groups A and B, 77 subjects (37 and 40, respectively) had at least 1 week-24, -36, or -96 evaluation with a reported time from the previous LPV/RTV dose. The median age (range) in years was 26 (18 to 30) in group A and 50 (45 to 79) in group B. The inter-subject mean of the intra-subject mean number of doses reported missed was 0.823 in group A and 0.248 in group B (p = 0.025). Based on the fitted model with age and dose history (imputing missed doses from the questionnaires), the predicted LPV clearances for a 30- and a 79-year-old were 6.332 L/hour and 4.277 L/hour, respectively, with the natural logarithm of the clearance rate decreasing 0.0080  (95%CI 0.0004 to 0.0156 L/hour) for every increase of 1 year in age (p = 0.042).

Conclusions:  In this example, older subjects reported better adherence than younger subjects.  After adjustments for adherence, age was negatively associated with LPV clearance rate, consistent with an age-related loss of CYP 3A4 activity.