Absorption, Metabolism, and Excretion of Darunavir, a New Protease Inhibitor, Administered Alone and with Low-Dose Ritonavir in Healthy Subjects

Abstract

ABSTRACT:Absorption, metabolism, and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of [ 14 C]-darunavir given alone (unboosted subjects) or with ritonavir [100 mg b.i.d. 2 days before and 7 days after darunavir administration (boosted subjects)]. Plasma exposure to darunavir was 11-fold higher in boosted subjects. Total recoveries of radioactivity in urine and feces were 93.9 and 93.5% of administered radioactivity in unboosted and boosted subjects, respectively. The most radioactivity was recovered in feces (81.7% in unboosted subjects and 79.5% in boosted subjects, compared with 12.2 and 13.9% recovered in urine, respectively). Darunavir was extensively metabolized in unboosted subjects, mainly by carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation and to a lesser extent by benzylic aromatic hydroxylation and glucuronidation. Total excretion of unchanged darunavir accounted for 8.0% of the dose in unboosted subjects. Boosting with ritonavir resulted in significant inhibition of carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation but had no effect on aromatic hydroxylation at the benzylic moiety, whereas excretion of glucuronide metabolites was markedly increased but still represented a minor pathway. Total excretion of unchanged darunavir accounted for 48.8% of the administered dose in boosted subjects as a result of the inhibition of darunavir metabolism by ritonavir. Unchanged darunavir in urine accounted for 1.2% of the administered dose in unboosted subjects and 7.7% in boosted subjects, indicating a low renal clearance. Darunavir administered alone or with ritonavir was well tolerated.Darunavir (TMC114, Prezista; Tibotec BVBA, Mechelen, Belgium) is an inhibitor of the human immunodeficiency virus (HIV) protease (Fig. 1). Its molecular formula is C 27 H 37 N 3 O 7 S ⅐ C 2 H 5 OH and molecular weight is 593. Darunavir is metabolized mainly by cytochrome P450 isozyme 3A (CYP3A) . As observed with other protease inhibitor (PIs) that are CYP3A4 substrates (Cooper et al., 2003;Zeldin and Petruschke, 2004), administration of darunavir with lowdose ritonavir as a pharmacokinetic booster results in clinically relevant increases in the systemic exposure to darunavir. Ritonavir is a potent CYP3A4 inhibitor, and inhibition of this isozyme in the intestinal tract and liver, where CYP3A4 exerts its effect on first-pass metabolism, reduces the metabolism of the parent drug, with a consequent increase in exposure to the unchanged drug.Darunavir is therefore administered in combination with low-dose ritonavir, and a dosing regimen of 600/100 mg b.i.d., used together with other antiretroviral agents, has been shown to be effective in decreasing the HIV-1 viral load in antiretroviral treatment-experienced adults, such as those with HIV-1 strains resistant to more than one PI (Clotet et al., 2007). On this basis, darunavir has received reg...

Low Frequency of Intermittent HIV-1 Semen Excretion in Patients Treated with Darunavir-Ritonavir at 600/100 Milligrams Twice a Day plus Two Nucleoside Reverse Transcriptase Inhibitors or Monotherapy

“…The unbound fraction of drug is considered the only effective fraction available for the diffusion or penetration into tissues. The darunavir plasma free fraction was 7.2% (5.9 to 9.0%) and was consistent with 95% protein binding primarily to plasma alpha 1-acid glycoprotein (21). There was a good correlation between darunavir total and free fractions of plasma proteins (r 2 ϭ 0.827; P Ͻ 0.0001).…”

“…Darunavir-ritonavir is an appropriate candidate for protease inhibitor (PI) monotherapy in maintenance therapy due to its high genetic barrier (5), high potency on naive and resistant HIV strains (11,15), and good pharmacokinetics profile (21). MONOI is an ongoing, 96-week, multicenter, randomized, open-label trial with a primary endpoint at week 48 (W48).…”

Boosting of HIV Protease Inhibitors by Ritonavir in the Intestine: The Relative Role of Cytochrome P450 and P-Glycoprotein Inhibition Based on Caco-2 Monolayers versus In Situ Intestinal Perfusion in Mice

“…Combined with our data obtained in the present study, these clinical findings support inhibition of presystemic LPV metabolism in human small intestine as a major mechanism underlying the pharmacokinetic boosting of LPV by RTV. In contrast to the 10-fold increase in LPV C max , RTV boosting resulted in a C max increase of only 49 to 77% for IDV (Hill et al, 2009) and 88% for DRV (Vermeir et al, 2009). This increase is lower, than would be expected based on our results obtained in the in situ perfusion experiments, suggesting that data obtained in mice regarding the effect of P-gp inhibition might somewhat overpredict the situation in humans.…”

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

“…Among the HIV PI that have been approved, lopinavir, atazanavir, darunavir and fosamprenavir are most frequently prescribed. 5,6 HIV PI are extensively metabolized by CYP3A enzymes 7,8 and their biliary excretion is mediated by the efflux transporters P-gp (ABCB1) and MRP2 (ABCC2). 8,9 In addition, it has been shown that some HIV PI (or their metabolites) are excreted via the feces for more than 75 %.…”