Lopinavir/Ritonavir Pharmacokinetic Profile: Impact of Sex and Other Covariates Following a Change From Twice‐Daily to Once‐Daily Therapy

Abstract

The aim of this study was to determine the impact of sex on the pharmacokinetics of lopinavir/ ritonavir. Interaction between lopinavir/ritonavir and tenofovir was also evaluated. Steady-state plasma samples were obtained from virologically suppressed HIV-infected patients on lopinavir/ ritonavir 800/200-mg soft gel capsule taken once daily. Drug assays were performed by highperformance liquid chromatography. Pharmacokinetic parameters estimated by noncompartmental method were reported as 90% confidence intervals (CIs) about the geometric mean ratio (GMR). There were 9 males and 11 females. No sex differences were observed in lopinavir/ritonavir pharmacokinetics profile. The GMR sex (women compared with men) for lopinavir area under the concentration-time curve (AUC 24 ), maximum concentration (C max ), and minimum concentration (C min ) was 0.95 (90% CI, 0.70-1.29), 0.88 (90% CI, 0.67-1.15), and 1.27 (90% CI, 0.60-2.66), respectively. Similarly, the GMR sex for ritonavir AUC 24 , C max , and C min was 0.84 (90% CI, 0.57-1.24), 0.79 (90% CI, 0.50-1.22), and 1.02 (90% CI, 0.58-1.80), respectively. Tenofovir coadministration led to a reduction in lopinavir/ritonavir plasma exposure, giving a lopinavir GMR tenofovir for C max of 0.72 (90% CI, 0.57-0.93) and AUC 24 of 0.74 (90% CI, 0.56-0.98), respectively. No difference in lopinavir/ritonavir plasma concentrations between sexes was demonstrated in this study. However, tenofovir coadministration lowered lopinavir/ritonavir plasma exposure. KeywordsGender-or sex-related differences; lopinavir pharmacokinetics Observation in antiretroviral (ARV) clinical pharmacology suggests that the same dose of an ARV drug produces varying plasma concentrations in different individuals attributable to interindividual differences in drug processing. This phenomenon of interindividual pharmacokinetic (PK) variability appears to occur across all classes of ARV drugs currently licensed for clinical use. Factors such as sex, race, age, body mass index, genetics, and the The plasma concentrations of saquinavir (SQV) when boosted with ritonavir (RTV), for example, have been shown to be significantly higher in women than in men. 6,7 Similarly, sex-related differences in plasma concentrations have been observed for nevirapine and efavirenz. 8,9 The intracellular triphosphate concentrations of zidovudine and lamivudine were recently reported to be different for men and women. 10 Because optimal virologic response often depends on achieving a threshold level of ARV exposure and drug toxicity is often directly correlated with plasma drug concentrations, the extent to which the PK profile of a given ARV agent varies with the sex of patients could have relevance in clinical HIV management.The primary objective of this study therefore was to assess the influence of sex on the steady-state PK profile of the fixed-dose combination of lopinavir and ritonavir (LPV/r) soft gel capsule formulation (SGC). The population studied included ARV-treated, virologically suppressed HIV-infected men and ...

Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

“…Total LPV (LPV t ) and RTV were measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection [8]. Free LPV (LPV f ) was quantitated using equilibrium dialysis followed by mass spectrometry.…”

Sex and Gender Differences in Infection and Treatments for Infectious Diseases

“…HIV PIs, for example, are generally highly, but variably, bound to AAG, thereby affecting the unbound (or active) concentration of the drug in plasma and tissues (Delille et al 2014). Some studies have noted higher plasma concentrations of certain PIs in women compared with men (Pai et al 2004;Fletcher et al 2004), but not others (Ofotokun et al 2007a). However, one study noted that changes in plasma AAG levels altered total but not free concentrations or the antiviral activity of the PI lopinavir (Ofotokun et al 2011), suggesting that sex-related changes in AAG may not affect a drug's pharmacodynamics effect.…”

Lopinavir/Ritonavir: A Review for 2011

“…13 Difference in patient gender has not been found to have an effect on LPV/r concentrations. 14 Exposure to LPV/r has been found to be lower in the third trimester of pregnancy, but further research has found that the standard dosage for pregnancy results in adequate therapeutic levels for antiretroviral suppression. 15,16 Administration of LPV/r oral liquid to pediatric patients results in a similarpharmacokineticprofiletothatobservedin adults.…”