HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects

Abstract

On the basis of the findings of this analysis, we conclude that, apart from bodyweight-based differences, both HIV/AIDS disease and sex affect efavirenz pharmacokinetics in Ugandans. HIV/AIDS disease is associated with reduced relative bioavailability of efavirenz. We recommend that findings from healthy subject studies be confirmed in HIV/AIDS patients and that caution be applied in direct extrapolation of exposure data to the target patient population.

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

“…Indeed, some ARVs (e.g., atazanavir and efavirenz) are reported to have lower plasma concentrations and bioavailability in HIV-infected subjects than in healthy volunteers (12,13). Other factors may also contribute to the observed pharmacokinetic differences, such as race, ethnicity, gender, age, diet, altered composition of the gastrointestinal lumen (e.g., pH differences), modified barrier integrity (e.g., tight junctional proteins), and/or interplay between intestinal drug uptake, efflux, and metabolism of ARVs (12,13). Furthermore, expression of drug transporters and enzymes may change over time, leading to progressive changes in tissue and plasma levels of ARVs in long-term-treated patients and resulting in late failure of a previously suppressive regimen.…”

“…Some ARVs (e.g., atazanavir and efavirenz) are also reported to have significantly different plasma pharmacokinetics in HIV-infected subjects and in healthy volunteers. This could potentially be due to the differences in the intestinal drug absorption associated with changes in drug metabolism and/or transport processes (12,13).…”

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV‐infected Ugandans

“…Factors reported to be associated with interpatient variability in efavirenz concentration include gender, ethnicity and genetic polymorphisms [3,4,7,8,36], while autoinduction and adherence [8,9] [3,4,7], while Black patients have been reported to exhibit lower rates of clearance of the drug and hence higher plasma concentrations [10]. A recent study comparing 24-h efavirenz pharmacokinetics between HIV-infected patients and healthy volunteers after a single dose showed patients with HIV/AIDS to have lower efavirenz oral bioavailability compared with healthy volunteers when genetics and gender were controlled for [11].…”

“…Factors reported to be associated with interpatient variability in efavirenz concentration include gender, ethnicity and genetic polymorphisms [3,4,7,8,36], while autoinduction and adherence [8,9] [3,4,7], while Black patients have been reported to exhibit lower rates of clearance of the drug and hence higher plasma concentrations [10]. A recent study comparing 24-h efavirenz pharmacokinetics between HIV-infected patients and healthy volunteers after a single dose showed patients with HIV/AIDS to have lower efavirenz oral bioavailability compared with healthy volunteers when genetics and gender were controlled for [11].Certain polymorphisms of the gene encoding the major enzyme responsible for efavirenz metabolism, CYP2B6 (an enzyme belonging to the cytochrome P450 group of liver enzymes), have been found to be associated with low clearance of the drug, resulting in high plasma concentrations [3,[12][13][14], and adverse reactions to efavirenz [15]. These polymorphisms, notably CYP2B6*6 and CYP2B6*11, are present at high frequencies in Black populations, causing slower clearance of the drug in a large proportion of individuals in these populations [4,7].…”

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…This study in healthy volunteers does not represent the clinical scenario, given that treatment of HIV is lifelong, and the long-term administration of EFV with its complex autoinduction phenomenon is not addressed. HIV/AIDS patients display lower relative bioavailability of efavirenz than healthy subjects, and hence direct extrapolation of efavirenz exposure data from healthy volunteers to the target patient population may not be applicable (8). Moreover, since most antiretroviral drugs, including efavirenz, exert their therapeutic effects in the target immune cells (15), characterization of the intracellular time course of these drugs may result in the design of a more accurate and reliable dosage regimen.…”