Efavirenz CNS toxicity during the initial phase of treatment may be related to Cmax, regardless of the sampling time. A plasma therapeutic range of 1–4 µg/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 [3–6]. 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] may contribute to both inter- and intrapatient variability. Female gender has been reported to be associated with higher efavirenz concentrations and a larger volume of distribution [3,4,7], while Black patients have

been reported to exhibit lower CT99021 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 C59 wnt clinical trial 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 [3,12–14], and adverse reactions to efavirenz [15]. These polymorphisms, notably CYP2B6*6 and CYP2B6*11, are present at high frequencies however in Black populations, causing slower clearance of the drug in a large proportion of individuals in these populations

[4,7]. A study conducted in the Netherlands with predominantly Caucasian participants reported 18.9% of participants with concentrations above the therapeutic range [3], while a study conducted among Zimbabweans in Africa showed that 50% of the study population exhibited efavirenz plasma concentrations above the therapeutic range [4]. Caucasians have subsequently been reported to have an average intrinsic hepatic clearance rate 28% higher than that of Africans and Hispanics [10]. In addition, other factors, including autoinduction, contribute to inter- and intraindividual variability in efavirenz pharmacokinetics. The clearance of efavirenz has been shown to increase from the baseline value as a result of autoinduction [8], although the timing and the extent to which efavirenz induces its own metabolism differ among studies. While Zhu et al. [8] observed a 2-fold increase in efavirenz clearance at steady state from baseline values, Kappelhoff et al.