A Review of Clinical Pharmacokinetic and Pharmacodynamic Profiles of Select Antiretrovirals: Focus on Differences among Chinese Patients

Abstract

OBJECTIVE To identify the pharmacokinetic differences of antiretroviral drugs between HIV-infected Chinese patients and patients of other race/ethnicities. STUDY DESIGN Results from prospective, open-label pharmacokinetic studies among Chinese and historical data from other race/ethnicities. PATIENTS Pharmacokinetics of six commonly used antiretroviral drugs, including zidovudine, lamivudine, tenofovir disoproxil fumarate, nevirapine, efavirenz and lopinavir/ritonavir, was evaluated in HIV-infected Chinese patients and compared with historical data from other race/ethnicities. ANALYSIS Pharmacokinetic analyses were performed at the steady state among HIV-infected Chinese patients. Safety data were collected during the follow-up. The pharmacokinetic parameters including maximal concentrations (Cmax), area-under-curve (AUC) and clearance (Cl/F) from the Chinese patients were compared to the historic data from other race/ethnicities. RESULTS Current evidence, though limited, suggested that these antiretroviral agents were generally safe and effective among HIV-infected Chinese patients. However, compared with other racial groups, Chinese patients exhibited higher C max , AUC and lower Cl/F for most of the agents, and the incidences of adverse reactions, for example, liver toxicity, rash, and bone health, were more frequent. CONCLUSIONS These pharmacokinetic differences suggest that lower dosages for commonly prescribed antiretroviral drugs in China might be appropriate to reduce drug-related adverse reactions, while maintain the antiviral efficacy.

Inter‐ethnic differences in pharmacokinetics—is there more that unites than divides?

“… 35 In Asian populations, the average body weight is 60 kg 36 which is significantly lower than many other populations. This is reflected with the drugs efavirenz 36 and selumetinib 37 where body weight was postulated as the underlying reason for the observed distribution differences seen between the studied populations (Table 1 ). Furthermore, lower body weight has also been considered a risk factor for increased systemic exposure of certain drugs such as tenofovir disoproxil fumarate (TDF) which may therefore provide justification for adjusting dosing regimens.…”

“…Furthermore, lower body weight has also been considered a risk factor for increased systemic exposure of certain drugs such as tenofovir disoproxil fumarate (TDF) which may therefore provide justification for adjusting dosing regimens. 36 Notably, no respondent mentioned inter‐ethnic differences in weight as an example of what they would teach their students on inter‐ethnic differences in PK.…”

“…Furthermore, in obese patients, tissue blood flow is decreased, and cardiac function and structure are modified 35 . In Asian populations, the average body weight is 60 kg 36 which is significantly lower than many other populations. This is reflected with the drugs efavirenz 36 and selumetinib 37 where body weight was postulated as the underlying reason for the observed distribution differences seen between the studied populations (Table 1).…”

Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2

“…Furthermore, the use of an empirical additional clearance component for the elimination of ritonavir, which in turn exerts a major influence on the systemic exposure of lopinavir, limited its mechanistic extrapolation to other populations (e.g., ethnic Han Chinese) with lower CYP450 enzyme expression levels. 9,10 Separately, a population PK model by Aspiroz et al 11 was recently utilized by Smith et al 12 to simulate the concentrations of lopinavir in plasma and lung and compared them with half-maximal effective concentration (EC 50 ) values of lopinavir against HIV, SARS-CoV, and MERS-CoV. However, it was a top-down model and included an empirical time-varying lopinavir clearance in order to simulate the effects of simultaneous inactivation and induction on steady-state levels.…”

“…Although a minimal PBPK model was previously reported for lopinavir/ritonavir, 8 it did not recapitulate the pharmacokinetic (PK) profile of the single dose administration of 400/100 mg lopinavir/ritonavir, as the model was optimized for a repeated dosing regimen. Furthermore, the use of an empirical additional clearance component for the elimination of ritonavir, which in turn exerts a major influence on the systemic exposure of lopinavir, limited its mechanistic extrapolation to other populations (e.g., ethnic Han Chinese) with lower CYP450 enzyme expression levels 9,10 . Separately, a population PK model by Aspiroz et al 11 .…”