Martine De Pauw

Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48

Background:The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients. Methods:Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks. Results:Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1 RNA: 4.85 log10 copies/ml and median CD4 count: 225 cells/μl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval −0.1–11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/μl) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2–4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%. Conclusion:DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients.

Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial

BACKGROUND The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients. METHODS Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877. FINDINGS Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients. INTERPRETATION In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population.

The Effect of Different Meal Types on the Pharmacokinetics of Darunavir (TMC114)/Ritonavir in HIV‐Negative Healthy Volunteers

This open‐label, randomized, crossover study investigated the bioavailability, short‐term safety, and tolerability of darunavir (TMC114) coadministered with low‐dose ritonavir under fasted conditions and after different meal types in HIV‐negative healthy volunteers. All volunteers received ritonavir 100 mg twice daily on days 1 to 5, with a single darunavir 400‐mg tablet given on day 3 (darunavir/rtv). Pharmacokinetic parameters for darunavir and ritonavir were determined under fasted conditions and following a standard breakfast, a high‐fat breakfast, a nutritional protein‐rich drink, or a croissant with coffee. Administration of darunavir/rtv in a fasting state resulted in a decrease in darunavir Cmax and AUClast of approximately 30% compared with administration after a standard meal. No significant differences in darunavir plasma concentrations were observed between different fed states. Darunavir/rtv should therefore be administered with food, but exposure to darunavir is not affected by the type of meal.

Pharmacokinetic Interaction between Darunavir Boosted with Ritonavir and Omeprazole or Ranitidine in Human Immunodeficiency Virus-Negative Healthy Volunteers

ABSTRACT Darunavir (DRV; TMC114; Prezista) is a human immunodeficiency virus (HIV) protease inhibitor used in combination with low-dose ritonavir (RTV) (DRV/r) as a pharmacokinetic enhancer. Protease inhibitor absorption may be decreased during coadministration of drugs that limit stomach acid secretion and increase gastric pH. This study was conducted to investigate the effect of ranitidine and omeprazole on the plasma pharmacokinetics of DRV and RTV in HIV-negative healthy volunteers. Sixteen volunteers completed the study and received DRV/r, DRV/r plus ranitidine, and DRV/r plus omeprazole, in three separate sessions. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Samples were taken over a 12-h period on day 5 for the assessment of DRV and RTV plasma concentrations. Pharmacokinetic parameters assessed included DRV area under the curve, maximum plasma concentration, and trough plasma concentration. The least-squares mean ratios and 90% confidence intervals are reported with treatment of DRV/r alone as a reference. Compared with DRV/r alone, no significant changes in DRV pharmacokinetic parameters were observed during coadministration of DRV/r and either ranitidine or omeprazole. Treatment regimens were generally well tolerated, and no serious adverse events were reported. In conclusion, coadministration of DRV/r and ranitidine or omeprazole was well tolerated by the volunteers. Ranitidine and omeprazole did not have a significant influence on DRV pharmacokinetics. No dose adjustments are required when DRV/r is coadministered with omeprazole or ranitidine.

Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers.

ABSTRACT The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC12h) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (Cmin) increased by 64% and the maximum plasma concentration (Cmax) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUCτ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.

Pharmacokinetics of darunavir/ritonavir and ketoconazole following co‐administration in HIV–healthy volunteers

AIMS To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV-healthy volunteers. METHODS Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. RESULTS Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC(12h)), maximum plasma concentration (C(max)) and minimum plasma concentration (C(min)) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC(12h), C(max) and C(min) increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC(12h), C(max) and C(min) increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. CONCLUSIONS The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.

Pharmacokinetic Interaction Between Darunavir and Saquinavir in Hiv-negative Volunteers

This was an open-label, crossover study to investigate the pharmacokinetic interaction between darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/ritonavir), and the protease inhibitor saquinavir in HIV-negative healthy volunteers. Thirty-two volunteers were randomized into two cohorts (panel 1 and panel 2). In two separate sessions, panel 1 received 400/100 mg darunavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day; panel 2 received 1000/100 mg saquinavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day. All treatments were administered orally under fed conditions for 13 days with an additional single morning dose on day 14. Treatment sessions were separated by a washout period of at least 14 days. Twenty-six volunteers completed the study (n = 14, panel 1; n = 12, panel 2), whereas six discontinued as a result of adverse events. Coadministration of saquinavir with darunavir/ritonavir resulted in decreases of darunavir area under the curve and maximum and minimum plasma concentrations of 26%, 17%, and 42%, respectively, compared with administration of darunavir/ritonavir alone. Relative to treatment with saquinavir/ritonavir alone, saquinavir exposure was not significantly different with the addition of darunavir. Ritonavir area under the curve12h increased by 34% when saquinavir was added to treatment with darunavir/ritonavir. The coadministration of darunavir/saquinavir/ritonavir was generally well tolerated. Similar findings are expected with the approved 600/100 mg darunavir/ritonavir twice-a-day dose. The combination of saquinavir and darunavir/ritonavir is currently not recommended.

Pharmacokinetics of Darunavir (TMC114) and Atazanavir during Coadministration in HIV-Negative, Healthy Volunteers

AbstractBackground and objective: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIVnegative, healthy volunteers. Methods: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout. Results: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens. Conclusion: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-infected patients.

Pharmacokinetic Interactions Between Darunavir/Ritonavir and Opioid Maintenance Therapy Using Methadone or Buprenorphine/Naloxone

271 U substance abuse is a common comorbidity among human immunodeficiency virus (HIV)–infected patients and can result in poor HIV treatment outcomes. The most effective treatment for opioid dependence is opioid maintenance therapy because it reduces opioid craving and helps to prevent the use of illicit drugs. Two of the most common maintenance therapies are methadone (METH) and, more recently, buprenorphine/naloxone (BUP/ NLX). Methadone is a synthetic narcotic analgesic that exists as Rand S-isomers. Only the R-enantiomer is biologically active, acting as an agonist at the opioid μ and δ receptors. Buprenorphine is a partial opioid receptor agonist with excellent sublingual resorption, whereas NLX is an opioid antagonist with very low sublingual resorption. The combination of these 2 agents provides an effective maintenance pharmacotherapy for opioid dependence when taken subligually, with an efficacy that is generally similar to that of METH. Interactions between antiretroviral (ARV) medications and opioid agonist maintenance therapies are of particular importance given the high prevalence of HIV infection among intravenous drug users. Several ARV agents have been shown to have pharmacologic interactions of potential clinical significance. For example, a substantial and clinically relevant decrease in METH concentrations was observed when METH was coadministered with the combination of the ARV lopinavir and low-dose ritonavir (LPV/r). Darunavir (DRV) is an HIV type 1 (HIV-1) protease inhibitor (PI) that is boosted with low-dose RTV (DRV/r) and has proven efficacy and safety in treatmentexperienced and treatment-naïve HIV-1-infected patients. DRV/r in combination with other ARVs is approved in the United States, European Union, and other countries for the treatment of HIV infection in adult and pediatric patients (6-18 years old). Pharmacokinetic drug–drug interactions between DRV/r and METH and between DRV/r and BUP/NLX may be expected based on their hepatic metabolism, because all of these drugs are metabolized by cytochrome P450 (CYP) 3A4. Methadone is primarily metabolized to an inactive metabolite, 2-ethylidene1,5-dimethyl-3,3-diphenylpyrrolidene, and the main (active) metabolite of BUP is norbuprenorphine (norBUP). Ritonavir (RTV) and DRV are inhibitors of CYP3A4 metabolism, with RTV being the more potent of the 2 inhibitors. Additionally, the isoenzyme CYP2B6 has a key role in METH clearance, and this enzyme is induced by RTV. Thus, DRV/r could potentially affect METH and BUP metabolism.

Darunavir/Ritonavir Pharmacokinetics Following Coadministration With Clarithromycin in Healthy Volunteers

This study investigated the steady‐state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low‐dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV‐negative healthy volunteers. In a 3‐way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14‐hydroxy‐clarithromycin plasma concentrations were reduced to below the lower limit of quantification (<50 ng/mL). The study medication was generally well tolerated. Based on these pharmacokinetic findings, neither clarithromycin nor darunavir/ritonavir dose adjustments are necessary when clarithromycin is coadministered with darunavir/ritonavir.