Cheri E. Klein

The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect.

Lopinavir, an HIV protease inhibitor, is coformulated with ritonavir to enhance the bioavailability and pharmacokinetics of lopinavir. The original solid oral formulation of lopinavir/ritonavir, a soft-gelatin capsule (SGC), requires refrigerated storage, is taken as 6 capsules daily at the recommended adult dose, and is administered with food to maximize the bioavailability of lopinavir. Melt extrusion technology was used to produce a tablet formulation reducing the number of dosage units administered per day and simplifying storage requirements. Three studies assessed the bioavailability of tablet doses of lopinavir/ritonavir at 800/200 mg or 400/100 mg under different meal conditions compared with equal doses of the SGC after a moderate-fat meal. The tablet was bioequivalent to the SGC after a moderate-fat meal with respect to lopinavir and ritonavir areas under the concentration-time curve. Compared with the SGC formulation, the tablet formulation resulted in more consistent lopinavir and ritonavir exposures within and across studies and across meal conditions. The diminished food effect and decreased variability of the tablet are likely to result in more consistent lopinavir and ritonavir exposures, minimizing the likelihood of extreme high or low values compared with the SGC.

Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers

Objective: The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF). Design: Open-label, multiple-dose, pharmacokinetic study in healthy volunteers. Methods: Subjects (n = 14) simultaneously received PO WARF 10 mg, vitamin K 10 mg, OMP 40 mg, CAF 2 mg/kg, and IV MDZ 0.025 mg/kg on days (D) 1 and 14, and PO MDZ 5 mg on D2 and D15. LPV/r (400/100 mg twice daily) was administered on D4-17. CYP2C9 and CYP2C19 activities were quantified by S-WARF AUC0-inf and OMP/5-hydroxy OMP ratio, respectively. CYP1A2, NAT-2, and XO activities were quantified by urinary CAF metabolite ratios. Hepatic and intestinal + hepatic CYP3A activities were quantified by IV (CL) and PO (CL/F) MDZ clearance, respectively. Results: After LPV/r therapy, CYP2C9, CYP2C19, and CYP1A2 activity increased by 29%, 100%, and 43% (P = 0.001, 0.046, and 0.001), respectively. No changes were seen in NAT-2 or XO activity. Hepatic and intestinal + hepatic CYP3A activity decreased by 77% (P < 0.001) and 92% (P = 0.001), respectively. Conclusion: LPV/r therapy results in modest induction of CYP1A2 and CYP2C9 and potent induction of CYP2C19 activity. Increasing doses of concomitant medications metabolized by these enzymes may be necessary. LPV/r inhibited intestinal CYP3A to a greater extent than hepatic CYP3A activity. Doses of concomitant CYP3A substrates should be reduced when combined with LPV/r, although intravenously administered compounds may require less of a relative dose reduction than orally administered compounds.

Effects of Acid‐Reducing Agents on the Pharmacokinetics of Lopinavir/Ritonavir and Ritonavir‐Boosted Atazanavir

A total of 71 HIV‐negative healthy adults were randomized to 1 of 6 regimens to receive lopinavir/ritonavir tablets 400/100 mg twice daily (bid) or 800/200 mg once daily (qd) or atazanavir 300 mg + ritonavir 100 mg qd from study days 1 to 15 with a moderate‐fat meal. One hour before breakfast, either omeprazole 40 mg qd was administered on study days 11 through 15, or a single dose of ranitidine 150 mg was administered on study day 11. Lopinavir, atazanavir, and ritonavir pharmacokinetics were determined on study days 10, 11, and 15 and compared using point estimates and 90% confidence intervals (CIs). The point estimates for lopinavir Cmax and AUCτ were in the range of 0.92 to 1.08, with 90% CI contained within the range of 0.80 to 1.25 after coadministration of omeprazole or ranitidine. The point estimates for atazanavir Cmax and AUCτ were decreased by 48% to 62% with the upper bound of the 90% CI 0.55 after coadministration of omeprazole or ranitidine. The results indicated that lopinavir bioavailability was not affected by the coadministration of omeprazole or ranitidine. In contrast, atazanavir bioavailability was decreased by 48% to 62% when coadministered with ritonavir and either omeprazole or ranitidine.

Predictors of Loss of Virologic Response in Subjects Who Simplified to Lopinavir/Ritonavir Monotherapy from Lopinavir/Ritonavir Plus Zidovudine/Lamivudine

Previous studies have demonstrated that lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a lopinavir/ritonavir-based combination regimen followed by simplification to lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4(+) T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA <50 copies/ml prior to simplification, and lopinavir concentrations. By the Cox proportional hazards model, higher reported adherence levels and higher baseline CD4(+) T cell counts were associated with a greater likelihood of maintaining virologic suppression while receiving lopinavir/ritonavir monotherapy. Lopinavir concentrations, including trough concentrations, were not significantly associated with virologic outcomes. This analysis suggests that adherence and higher baseline CD4(+) T cell counts may help to predict who will sustain virologic suppression with lopinavir/ritonavir monotherapy. The data also suggest that measuring lopinavir concentrations is not useful in predicting virologic response in these patients.

High-Dose Lopinavir/Ritonavir in Highly Treatment-Experienced HIV-1 Patients: Efficacy, Safety, and Predictors of Response

Abstract Objective: To investigate the efficacy and safety of high-dose lopinavir/ritonavir (LPV/r) therapy in multiple protease inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced subjects. Method: Thirty-six HIV-1-infected subjects were randomized to LPV/r 400/300 mg or 667/167 mg bid in a 48-week, open-label study. Subjects also received investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs). Primary outcomes were the proportion of subjects with HIV-1 RNA levels <50 copies/mL at week 24 and time until loss of virologic response through week 48. Results: Six of 17 (35%) and 10 of 19 (53%) subjects in the 400/300 and 667/167 groups, respectively, completed 48 weeks of treatment. Median durations of follow-up in discontinued subjects and all subjects were 15 weeks and 32 weeks, respectively. Forty-four percent of subjects achieved HIV-1 RNA <50 copies/mL at least once; 18% (400/300 mg) and 21% (667/167 mg) of subjects achieved HIV-1 RNA <50 copies/mL at week 24 (intent-to-treat analysis). Corresponding results at week 48 were 18% (400/300 mg) and 26% (667/167 mg). No statistically significant differences in adverse event incidence occurred between treatment groups, except for a higher vomiting rate in the 400/300 mg dose group. Predictors of response included baseline LPV inhibitory quotient and number of active NRTIs. Conclusion: Higher doses of LPV/r may provide substantial antiviral activity in multiple class-experienced subjects.

Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women

Context Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. Objective We evaluated the pharmacokinetics and pharmacodynamics of elagolix. Design, Setting, and Participants This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Interventions Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main Outcome Measures Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Results Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Conclusions Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women.

The effect of food on ritonavir bioavailability following administration of ritonavir 100 mg film-coated tablet in healthy adult subjects

Methods This was a single-dose, open-label, 3-period crossover study with a randomized, crossover design. Healthy male and female subjects (n = 27) participated in the study. Serial blood samples were collected for 36 hours after each dose. Ritonavir AUC from time 0 to the last measurable concentration (AUCt) and from time 0 to infinity (AUCinf), maximum plasma concentration (Cmax), and time of Cmax (Tmax) were determined using noncompartmental methods. The bioavailability of the tablet following a meal relative to the fasting condition was assessed by the two one-sided tests procedure using 90% confidence intervals (CI). Safety was assessed throughout the study.

Pharmacokinetics and Safety of the Lopinavir/Ritonavir Tablet 500/125 mg Twice Daily Coadministered With Efavirenz in Healthy Adult Participants

A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (Cmax), plasma concentration prior to morning dosing (Ctrough), and area under the plasma concentration‐time curve over a dosing interval (AUC12) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone.

Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis

IntroductionElagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters.MethodsThe data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis.ResultsElagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F.ConclusionElagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis.Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

Relationship Between Atrasentan Concentrations and Urinary Albumin to Creatinine Ratio in Western and Japanese Patients With Diabetic Nephropathy

PURPOSE The objective of the current analyses was to characterize the pharmacokinetic properties of atrasentan and the exposure-response relationships for the efficacy end point, urinary albumin to creatinine ratio (UACR), and the treatment-emergent adverse event, peripheral edema, during 8 or 12 weeks of treatment. METHODS Results from 3 Phase II, randomized, double-blind, placebo-controlled studies (N = 257) were used for the population pharmacokinetic and exposure-response models. Concentration-time and response data for efficacy and tolerability were analyzed using a nonlinear mixed-effects population analysis and logistic regression approaches. FINDINGS The pharmacokinetic data were adequately described by a 2-compartment model with first-order absorption and elimination. After weight was accounted for, no clinically meaningful differences were found in CL/F or Vd/F of the central compartment between Western and Japanese patients. Exposure-response analyses confirmed the efficacy of atrasentan in reducing UACR, with an estimated decrease in UACR of ≥37% when the atrasentan dose was 0.75 mg or higher. No significant association between atrasentan exposure and the rate of edema was identified at atrasentan doses of 0.5, 0.75, and 1.25 mg. The rates of peripheral edema were comparable in patients receiving active treatment and placebo. IMPLICATIONS The exposure-response relationships for efficacy and tolerability were consistent between Western and Japanese patients. On the basis of these analyses, a dose of 0.75 mg/d was selected for the Phase III trial. ClinicalTrials.gov identifiers: NCT01356849, NCT01399580, and NCT01424319.