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

Abstract

BackgroundPharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans. MethodsEfavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenzbased regimens, with blood samples collected at eight time-points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz. ResultsThe mean steady-state minimum plasma concentration (C min ) of efavirenz was 2.9 mg/mL, the mean area under the curve (AUC) was 278.5 h mg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C max ) of efavirenz was 44 mg/ mL in 96.6% of participants, while C min was o1 mg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2-week period, and 95% of these participants were found to have efavirenz plasma concentrations 44 mg/mL, although only half maintained a high concentration until at least 8 h after dosing. ConclusionThe findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C max , regardless of the sampling time.Keywords: autoinduction, efavirenz, pharmacokinetics, Ugandans IntroductionA plasma therapeutic range of 1-4mg/mL has been established for the nonnucleoside reverse transcriptase inhibitor efavirenz [1,2], and great variation in the pharmacokinetics of the drug exists within and between patients, causing variation in drug concentrations [3][4][5][6]. 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 ...

In Vitro–In Vivo Correlation of Efavirenz Tablets Using GastroPlus®

“…However, there is variability among individuals included in this study as mentioned by other groups in the literature (37)(38)(39)(40)(41)(42). Thus, physiological differences including variable enzyme expression, blood perfusion into tissues, and tissue volume may explain the low CL value in our model, which is still within the range of values reported.…”

HIV Associated Neurocognitive Disorders (HAND) in Malawian Adults and Effect on Adherence to Combination Anti-Retroviral Therapy: A Cross Sectional Study

“…Additionally, those with higher drug levels may experience neurotoxicity secondary to cART side effects [35]. In particular, high plasma levels of efavirenz are associated with an increase in neuropsychiatric disease [36], [37]. However the number of patients on efavirenz was small and we did not observe increased rates of HAND or higher GDS scores in this group compared to those taking nevirapine.…”

Differential activation of human constitutive androstane receptor and its SV23 and SV24 splice variants by rilpivirine and etravirine

“…The CYP2B6 enzyme metabolizes a diverse group of drugs, including bupropion (Hesse et al ., ), efavirenz (Ward et al ., ), and nevirapine (Erickson et al ., ). The CYP2B6‐inducing concentrations of rilpivirine (0.5–5.0 μM), etravirine (2.5–5.0 μM), and efavirenz (5–10 μM) evident in our sandwich‐cultured human hepatocyte experiment are comparable with the steady‐state maximum plasma concentrations reported for rilpivirine (0.30 ± 0.08 μM; mean ± SD) (Goebel et al ., ), etravirine (up to 5 μM) (Gagliardini et al ., ), and efavirenz (12.98 μM; 95% confidence interval, 7.95–18.27 μM) (Nanzigu et al ., ). Whether rilpivirine and etravirine influence the elimination pharmacokinetics of CYP2B6‐metabolized drugs is not known, but efavirenz has been reported to decrease by approximately one‐half the systemic exposure to bupropion (i.e.…”