Intracellular and plasma steady‐state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre‐treated HIV‐infected patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre-treated for HIV-infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS• We investigated the steady-state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment. AIMTo study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODSPatients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTSIrregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l -1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONSThe observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK-PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance.

Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

“…The intracellular-to-plasma ratios for RAL were only 0.11 to 0.24 in our study using two different methods of estimation. This result is consistent with other studies of HIV patients on standard doses (19) and an 800-mg once daily (15) dose of RAL. This result is also consistent with simple diffusion of unbound RAL into cells, based on protein binding of 83% in plasma (14).…”

“…On the other hand, at least two studies reported that a one-compartment model provided an adequate data fit. Our healthy subjects had lower population mean (%RSE) CL/F, 39.1 (20.8%) liters/h compared to 264 (23%) and 191 (16%) liters/h in the study of Dickinson et al (4) and Ter Heine et al (19), respectively. For V/F, our study yielded 272 (21.8%) liters in comparison with 820 (25.5%) (4) and 76 (8%) liters (19).…”

“…Our healthy subjects had lower population mean (%RSE) CL/F, 39.1 (20.8%) liters/h compared to 264 (23%) and 191 (16%) liters/h in the study of Dickinson et al (4) and Ter Heine et al (19), respectively. For V/F, our study yielded 272 (21.8%) liters in comparison with 820 (25.5%) (4) and 76 (8%) liters (19). However, differences in sample sizes, subject type (healthy subjects or HIV patients), and dosage forms of RAL could have accounted for the variability in parameter estimates.…”

“…The intracellular-to-plasma ratios for etravirine, darunavir, and ritonavir were 12.9, 1.32, and 7.72, respectively (19). The intracellular-to-plasma ratios for RAL were only 0.11 to 0.24 in our study using two different methods of estimation.…”

“…Furthermore, a secondary peak for one subject was much higher than for the other subjects. This phenomenon could be caused by the combined effect of delayed absorption in the gastrointestinal tract and enterohepatic circulation (19). The delayed absorption may be due to individual differences in gastric emptying time.…”