Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets

Abstract

Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C 0 ) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC 0-12 ), C 0 , C 12 , maximum concentration of drug in serum (C max ), or half-life (t 1/2 ) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies.Rifampin is a key component of tuberculosis treatment but also a potent inducer of many cytochrome P450 enzymes and the efflux pump p-glycoprotein (15). Protease inhibitors are substrates of both CYP 3A4 and p-glycoprotein, and the trough concentrations of all ritonavir-boosted protease inhibitors are reduced by more than 90% when standard doses are coadministered with rifampin (2). A healthy-volunteer study demonstrated that similar lopinavir (LPV) trough concentrations can be achieved either by adding ritonavir (RTV) to give a lopinavir/ritonavir ratio of 1:1 or by doubling the dose of the capsule formulation of lopinavir-ritonavir (LPV/r) (12).Subsequent healthy-volunteer studies of the interaction between rifampin and adjusted doses of ritonavir-boosted saquinavir, atazanavir, and lopinavir (tablet formulation) were prematurely terminated because of high incidences of hepatotoxicity (6, 7, 16). These high rates of hepatotoxicity in healthy volunteers might not apply to patients with tuberculosis and HIV. First, in the healthy-volunteer studies, initiating rifampin prior to the protease inhibitor was associated with high rates of hepatotoxicity (6,7,16). In high-burden countries, protease inhibitors are used as part of the second-line antiretroviral treatment (ART) regimen; hence, most patients are established on the protea...

Association of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study

“…We found the median lopinavir concentration was 8 μg/mL, which is higher than reported elsewhere [17,18], but comparable to the trough concentrations after observed doses in a study conducted by our group from the same community [19]. Lopinavir pharmacokinetics demonstrate considerable interindividual variability, which may affect treatment outcomes.…”

Population Pharmacokinetics of Lopinavir and Ritonavir in Combination with Rifampicin-Based Antitubercular Treatment in HIV-Infected Children

“…However, implementation of ‘super-boosted’ LPV is not practical in many settings as it is complex to prescribe and administer, and ritonavir solution has a short shelf life, hence clinics frequently run out of stock. An alternative approach using double doses of LPV/r achieved adequate concentrations of LPV in adults given rifampicin concurrently [2,5], but results in trough concentrations of LPV below the minimum recommended concentration in the majority of young children [6]. …”

Pharmacokinetics and 48 Week Efficacy of Adjusted Dose Indinavir/Ritonavir in Rifampicin-Treated HIV/Tuberculosis-Coinfected Patients: A Pilot Study

“…Only one retrospective study showed that in patients using nonadjusted dosing of lopinavir/ritonavir with rifampicin (n = 23), 40 62% had undetectable HIV RNA and 17% had adverse events while 40% of patients on a recommended dose of lopinavir/ritonavir (n = 5) had to prematurely stop lopinavir/ritonavir due to adverse events. Recently, a report from a South African collaborative group (n = 21) 41 suggested doubling the dose of LPV/r so that the concentrations of lopinavir will be sufficient as well as tolerable, which resulted in having only two patients who developed asymptomatic hepatitis. ) with and without rifampicin.…”