EFAVIRENZ AS AN ANTIRETROVIRAL AGENT
2.9 Pharmacokinetics of EFV
The pharmacokinetics of EFV has been studied in rats, monkeys [108] and humans [109]. In rats and monkeys, EFV exhibited nonlinear pharmacokinetics within the relatively high range of dosing used, which was aggravated by delayed gastric-emptying in these species and saturable metabolic processes [108]. In humans, the delay in gastric emptying is not significant because the dosing is once daily, hence the amount of drug in the body remains within the linear range.
2.9.1 Absorption
EFV is well absorbed after the oral administration to humans. Only less than 1% of an oral dose is excreted in urine and faeces. Peak plasma concentrations are reached within 5 hr of
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dosing and the drug’s pharmacokinetics is linear with plasma concentrations increasing with increasing dose.
2.9.2 Effect on P-glycoprotein
The effect of EFV on P-gp activity has been assessed on different cells and yielded different results. In canine kidney cell lines, EFV was found to inhibit multi-drug resistance proteins [110], while it was found to induce P-gp in peripheral blood mononuclear cells isolated from healthy volunteers [111]. In an in vitro study on Caco-2 cells undertaken by Stӧrmer et al [112], EFV was found to be a weak inducer of P-gp, and, therefore, less likely to affect drug efflux. The effect of EFV on P-gp activity on immortalised rat brain cell line has been found not to be significant, and EFV uptake through the blood-brain barrier of adult male Wistar rats was not affected by P-gp inhibitors [113]. In another study by Berruet et al [114], EFV was found not to be an inducer or inhibitor in rats. Mouly et al [115] assessed the effect of EFV on intestinal P-gp, and found that the effect of EFV on P-gp was not detectable, hence no clear conclusion was reached. Thus, the effect of EFV on P-gp is still not well established.
2.9.3 Distribution
Lipophilicity of EFV renders it highly distributed in the body. EFV has been found in various sites and cells in the body such as the microglia, semen, lymphocytes and peripheral blood mono-nuclear cells. In a population pharmacokinetic meta-analysis involving 334 healthy human volunteers from phase 1 clinical studies, the apparent volume of distribution (Vd/F) after a single and multiple doses were 151 L and 190 L, respectively [116]. In another population pharmacokinetic study involving 235 HIV positive patients from a cohort of patients on EFV based regimens, Vd/F was found to be 252 ± 14% [117]. From these two studies, it can be concluded that EFV is widely distributed in the body. Almond et al [118]
found that the ratio of intracellular EFV AUC0-24 to unbound EFV AUC0-24 was over 200, which showed that there is more unbound EFV in the intracellular spaces than in plasma. In a study where 11 patients on EFV were assessed for penetration of EFV into the CSF, EFV was not detectable but this method does not state the lower limit of quantitation (LLOQ), of the LC/MS method [119]. EFV has a high affinity for adipose tissues in humans [120] due to its lipohilicity.
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EFV is a substrate of the cytochrome P450 (CYP450) enzyme family, in particular CYP2B6 and CYP3A4. Metabolism of EFV has been studied in cynomologous monkeys, guinea-pigs, hamsters, humans and rats, and EFV was found to be extensively metabolised in all these species [109]. There are some differences and similarities in the metabolism between species.
In humans, metabolites were mainly found in urine, while plasma samples showed mostly unchanged EFV. Seven metabolites were found in human urine (Figure 2.5) [109], and six were found in plasma. Oxidative hydroxylation at three positions in the EFV molecule is the main mechanism of metabolism. These metabolites then undergo phase II conjugation, and this is where there are significant differences between species. In humans the preferential route is conjugation with glucuronic acid at C8, whereas in rats, it was sulphuric acid. The main metabolites are the glucuronide conjugates of 8-hydroxyefavirenz and 7- hydroxyefavirenz after multiple dosing, while the N-glucuronide conjugate of EFV was the major metabolite after single dosing. The structures of these metabolites were confirmed by mass spectroscopy (MS) and nuclear magnetic resonance (NMR).
In one in vitro study using human liver microsomes (HLMs), CYP2B6 was determined as the main enzyme involved in the metabolism of EFV [121]. Primary metabolites of EFV were found to be 8-hydroxyefavirenz (main) and 7-hydroxyefavirenz (minor), and 8,14- dihydroxyefavirenz (secondary) in the in vitro study. The formation of 8,14- dihydroxyefavirenz showed a longer lag-time relative to formation of 8-hydroxyefavirenz. It was confirmed that the formation of 8,14-dihydroxyefavirenz followed a step-wise hydroxylation of EFV, with 8-hydroxyefavirenz as an intermediate. Metabolites of EFV were evaluated for antiretroviral activity, and it was found that none of them exhibited any antiretroviral activity [122].
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Figure 2.5. Proposed metabolic pathway for EFV in humans [109].
The clearance of EFV is higher in Caucasians than in Blacks and Asians [123]. This phenomenon can be caused by variability in the gene expressing CYP2B6. Prevalence of homozygous CYP2B6 */*6 allele among West Africans and African-Americans were found to be higher than Caucasians, Asians and Hispanics [124]. Ståhle et al [125] found high intra- and inter-patient variability in plasma EFV concentrations, with inter patient variability reaching 84%. It was suggested that the high variability could be caused by polymorphism exhibited by CYP2B6. Patients with the homozygous CYP2B6 */*6 allele have been found to have higher plasma concentrations than those with heterozygous *6, or those without the *6 allele [126, 127]. Patients with the homozygous recessive allele are at higher risk of developing adverse events from high EFV plasma concentrations. There is thus a higher probability that patients with the homozygous CYP2B6 */*6 allele will experience more prolonged EFV plasma exposure following discontinuation of therapy [104]. This could lead to the undesirable situation of EFV monotherapy on discontinuation of the ARV regimen.
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Therefore, it is important that patients do not discontinue therapy or take holidays from therapy unless a proper plan has been made by clinicians.
The elimination half-life of EFV after single and multiple oral doses is 55-76 hr and 40-55 hr, respectively, the latter being because EFV induces its own metabolism. EFV can induce or inhibit CYP3A4, thereby affecting plasma concentrations of CYP3A4 substrates [115].
Conjugated oxidative metabolites are excreted in bile and in urine [109]. Only less than 1% is excreted unchanged in urine and faeces.