Ritonavir Plasma Concentrations Research Articles

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults.

The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.

Pharmacokinetics, Safety, and Bioequivalence of 2 Lopinavir/Ritonavir (200/50mg) Tablets in Healthy Chinese Volunteers: Effect of Food on Absorption.

Lopinavir/ritonavir is an important protease inhibitor for treating HIV-1 infection in patients aged >2 years in combination with other antiretrovirals. The antiviral activity of lopinavir/ritonavir in vivo is mainly derived from lopinavir, while ritonavir improves the bioavailability of lopinavir. This study compared the bioequivalence and safety of 2 lopinavir/ritonavir (200/50mg) formulations under fasted and fed conditions in healthy Chinese volunteers and compared the pharmacokinetic parameters of lopinavir and ritonavir. A randomized, open-label, single-dose, 4-period, crossover bioequivalence was conducted in 72 subjects under fasted and fed conditions. Lopinavir and ritonavir plasma concentrations were analyzed using validated liquid chromatography with tandem mass spectrometry. Noncompartmental analysis was used to evaluate pharmacokinetic parameters. The 90% confidence intervals of test/reference geometric mean ratio for lopinavir and ritonavir area under the plasma concentration-time curve and maximum drug concentration meets the bioequivalence criteria based on the average bioequivalence method. A high-fat meal delayed the time to the maximum concentration of lopinavir and ritonavir. Therefore, these formulations were bioequivalent in healthy Chinese volunteers under fasting and fed conditions. Moreover, adverse events were more frequent in the fed state, but all were mild.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir–interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. MethodsWe conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. ResultsThe intention-to-treat population included 583 participants—lopinavir/ritonavir (n = 145), lopinavir/ritonavir–IFN–β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)—among whom 418 (71.7%) were male, the median age was 63 years (IQR 54–71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55–1.26, p 0.39), lopinavir/ritonavir–IFN–β-1a versus control, aOR 0.69 (95%CI 0.45–1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62–1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir–IFN–β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

BackgroundThe combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000–8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir.ObjectivesTo assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir.Patients and methodsMechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100 mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100 mg q24h was proposed if lopinavir Ctrough was >8000 ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored.ResultsPlasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27 908 ng/mL (15 928–32 627). After the dose reduction to 400/100 mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22 974 ng/mL (21 394–32 735).ConclusionsIn mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed.

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir.

Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.

Darunavir Pharmacokinetics With an Increased Dose During Pregnancy.

This study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum. Darunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2-3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography. Target darunavir area under the concentration time curve (AUC) was >70% (43.6 μg × h/mL) of median AUC (62.3 μg × h/mL) in nonpregnant adults on twice daily darunavir-ritonavir 600/100 mg. Twenty-four women were included in the analysis. Darunavir AUC0-12 was lower with the increased dose during the second {[geometric mean ratio (GMR) of 0.62 (IQR 0.44-0.88); P = 0.055]} and third trimesters [GMR 0.64 (IQR 0.55-0.73); P = <0.001] compared with postpartum. Darunavir apparent clearance was higher during the second [GMR 1.77 (IQR 1.24-2.51); P = 0.039] and third trimesters [GMR 2.01 (IQR 1.17-2.35); P = <0.001] compared with postpartum. Similarly, ritonavir AUC0-12 was lower during the third trimester [GMR 0.65 (IQR 0.52-0.82); P = 0.007] compared with postpartum, whereas its apparent clearance was higher during the third trimester [GMR 1.53 (IQR 1.22-1.92); P = 0.008] compared with postpartum. No major drug-related safety concerns were noted. Increasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared with 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.

Pharmacokinetics of plasma lopinavir and ritonavir in tuberculosis\u2013HIV co-infected African adult patients also receiving rifabutin 150 or 300\xa0mg three times per week

BackgroundTo evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and HIV co-infected adult patients.MethodsThis is a pharmacokinetic study conducted in Ouagadougou among patients treated with a standard dosage of LPV/RTV 400/100 mg twice daily and RBT 150 mg TPW (arm A = 9 patients) or rifabutin 300 mg TPW (arm B = 7 patients) based regimens. Patients were recruited from the Bogodogo and Kossodo district hospitals in Ouagadougou from May 2013 to December 2015. Study inclusion criteria were that the patients were between 18 and 60 years of age, HIV-1 infected with pulmonary tuberculosis confirmed or suspected. Subsequent blood samples for pharmacokinetic monitoring were collected at 1, 2, 3, 4, 6, 8 and 12 h after combined drug ingestion for plasma drug monitoring using HPLC/MS assays.ResultsThe medians LPV Cmax and Tmax were respectively, 20 μg/mL and 4 h for the RBT 150 mg group (arm A) and 7.7 μg/mL and 3 h for the RBT 300 mg group (arm B). The AUC0–12 of LPV was 111.8 μg h/mL in patients belonging to arm A versus 69.9 μg/mL for those in arm B (p = 0.313). The C0 of LPV was lower than 4 μg/mL in three patients receiving RBT 300 mg. Of note, the RTV plasma concentrations were nearly halved among patients on RBT 300 mg compared to those on lower RBT doses. The AUC0–12 of RTV in arm A was 12.7 μg h/mL versus 6.6 μg h/ml in arm B (p = 0.313).ConclusionIn our study, the pharmacokinetic of LPV and RTV was found to be highly variable when coadministrated with RBT 150 mg or 300 mg three times per week. There is a need for specific large study to verify clinical and virological effects of this variation, especially when coadministrated with RBT of 300 mg TPW, and to prevent viral resistance in response to under-dosing of LPV.Trial registration PACTR201310000629390. Registered 28 October 2013, http://www.pactr.org/

Therapeutic drug monitoring of boosted PIs in HIV-positive patients: undetectable plasma concentrations and risk of virological failure

Therapeutic drug monitoring (TDM) of antiretroviral drugs is performed in selected HIV-positive patients. The aim of this study was to estimate the prevalence of undetectable plasma concentrations of ritonavir and boosted PIs and to evaluate the association between those and the 48 week risk of virological failure. A TDM registry study and a retrospective follow-up study were conducted. Plasma concentrations were measured through validated methods. According to PI and ritonavir concentrations, patients were stratified as adherent, partially non-adherent or non-adherent. Virological outcome was evaluated 48 weeks afterwards. The TDM registry study included 2468 samples collected from 723 patients (68.1% male, median age 43.5 years). Eighty-seven samples (3.5%, 74 patients) and 68 samples (2.8%, 52 patients) were in the partially non-adherent and non-adherent groups, respectively; more patients on atazanavir/ritonavir (7.9%) versus darunavir/ritonavir (2% twice daily and 1.9% once daily) and lopinavir/ritonavir (1.5%; P < 0.001) were observed in the partially non-adherent group. Two hundred and ninety patients were included in the follow-up study (64.1% male, median age 40 years). Patients in the adherent group had a higher chance of viral control [81.9% (167/204)] versus the partially non-adherent group and the non-adherent group [71.7% (33/46) and 53.1% (17/32), respectively; P = 0.001]. Based on multivariate analysis, baseline HIV RNA >50 copies/mL ( P < 0.001), genotypic susceptibility score ≤2 ( P = 0.001), lower nadir CD4 cell count ( P = 0.003) and not being in the adherent group ( P = 0.029) were independent predictors of HIV RNA >50 copies/mL at 48 weeks. The measurement of PI and ritonavir plasma levels can uncover incomplete compliance with treatment; TDM may represent a useful tool for identifying patients in need of adherence-promoting interventions.

Population pharmacokinetic modelling of the changes in atazanavir plasma clearance caused by ritonavir plasma concentrations in HIV-1 infected patients.

The aim of the present study was to develop a simultaneous population pharmacokinetic model for atazanavir (ATV) incorporating the effect of ritonavir (RTV) on clearance to predict ATV concentrations under different dosing regimens in HIV-1-infected patients. A Cross-sectional study was carried out in 83 HIV-1-infected adults taking ATV 400mg or ATV 300mg/RTV 100mg once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed-effects modelling and used to simulate six dosing scenarios. The selected one-compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63mg l-1 predicted an 18% decrease in ATV clearance. The percentages of patients with an end-of-dose-interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15mg l-1 and 0.85mg l-1 favoured the selection of the simulated ATV/RTV once-daily regimens (ATV 400mg, ATV 300mg/RTV 100mg, ATV 300mg/RTV 50mg, ATV 200/RTV 100mg) over the unboosted twice-daily regimens (ATV 300mg, ATV 200mg). A one-compartment simultaneous model can describe the pharmacokinetics of RTV and ATV, including the effect of RTV plasma concentrations on ATV clearance. This model is promising for predicting individuals' ATV concentrations in clinical scenarios, and supports further clinical trials of once-daily doses of ATV 300mg/RTV 50mg or ATV 200mg/RTV 100mg to confirm efficacy and safety.

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment

BackgroundWhile studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART.MethodsART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005–2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata.ResultsA total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r.ConclusionsSex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences.Trial registrationClinicalTrials.gov Identifier: NCT00117728

Short Communication: Aging Not Gender Is Associated with High Atazanavir Plasma Concentrations in Asian HIV-Infected Patients

Physiological effects of aging make the older population more susceptible to adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks. Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC(0-24) 71.2 vs. 53.1 mg·h/liter, C(max) 8.5 vs. 5.5 mg/liter, and C(trough) 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV C(trough) levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.

Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV‐1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily

ObjectivesAntiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women.MethodsHIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using 14C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis.ResultsData were available for 14 women. The area under the plasma concentration–time curve from 0 to 12 h (AUC12h) for total darunavir was 17–24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43–86% and 10–14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73–90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature.ConclusionsTotal darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.

Intracellular accumulation of ritonavir combined with different protease inhibitors and correlations between concentrations in plasma and peripheral blood mononuclear cells

Ritonavir, used at low doses as a boosting agent of other protease inhibitors (PIs), is known to be associated with metabolic complications and gastrointestinal disturbances. The rate of accumulation of ritonavir within cells is still debated due to scarce data and methodological limitations. Therefore, our aim was to evaluate intracellular ritonavir penetration when used with different boosted PIs in the clinical setting. Patients administered with atazanavir/ritonavir (300/100 mg, once daily), darunavir/ritonavir [600/100 mg, twice daily (darunavir-600) and 800/100 mg, once daily (darunavir-800)], lopinavir/ritonavir (400/100 mg, twice daily) and tipranavir/ritonavir (500/200 mg, twice daily) were considered. Blood sampling at the end of the dosing interval (Ctrough) was performed. Peripheral blood mononuclear cell (PBMC)-associated and plasma ritonavir and PI concentrations were measured by validated HPLC methods. PBMC count and individual mean cell volume (MCV) were measured using a Coulter Counter instrument. One hundred patients were enrolled. Frequencies of ritonavir-boosted PIs were atazanavir, 37%; darunavir-600, 23%; lopinavir, 19%; tipranavir, 13%; and darunavir-800, 8%. The median intracellular and plasma concentrations of ritonavir were 1279 ng/mL (IQR 727-2087) and 170 ng/mL (IQR 82-384), respectively, accounting for a cellular accumulation ratio of 7.69 (5.7-10.9). Significant differences in ritonavir intracellular concentrations emerged among different PIs (P<0.001): specifically between darunavir-600 and atazanavir (P<0.001), between darunavir-600 and tipranavir (P=0.009), between atazanavir and lopinavir (P<0.001) and between lopinavir and tipranavir (P=0.027). Our study showed a higher rate of ritonavir intracellular accumulation than previously reported, possibly due to the more accurate calculation of intracellular concentrations by MCV. The ratio varied according to concomitantly administered PIs, suggesting their influence on the rate of ritonavir intracellular penetration.

Ritonavir boosting dose reduction from 100 to 50 mg does not change the atazanavir steady-state exposure in healthy volunteers

To evaluate the pharmacokinetics, tolerability and safety of 300 mg of atazanavir boosted with 100 or 50 mg of ritonavir, both once daily, at steady state. This was a single-blind, multiple-dose, crossover, sequence-randomized trial. Thirteen healthy HIV-1-negative men received witnessed once-daily doses of atazanavir (300 mg) and 100 or 50 mg of ritonavir for 10 days (15 day washout). Atazanavir and ritonavir plasma concentrations were determined for 24 h on day 10. Log-transformed individual pharmacokinetic parameters were compared between treatments (analysis of variance); the difference between treatments on the log scale and 95% CIs were calculated. Fasting cholesterol, triglycerides, glucose and bilirubin plasma levels were measured at the beginning and end of each period and compared (Wilcoxon signed rank test). Gastrointestinal symptoms and other events were recorded. Ritonavir C(max) and the AUC₀₋₂₄ were lower after the 50 mg booster dose than after 100 mg [geometric mean ratio (GMR) (95% CI), 0.40 (0.31-0.51) and 0.35 (0.29-0.42), respectively]. No differences were observed in atazanavir exposure with 50 or 100 mg of ritonavir [GMR C(max) (95% CI), 1.00 (0.79-1.28); GMR AUC₀₋₂₄ (95% CI), 0.98 (0.79-1.21)]. Atazanavir trough concentration was >0.15 mg/L in all volunteers. Total and low-density lipoprotein cholesterol increased 0.40 mM (P = 0.01) and 0.37 mM (P = 0.003) from their corresponding baseline value during the 100 mg dosing period; there were no significant changes on 50 mg. Mild increases in bilirubin were detected on day 10 after both treatments without differences between treatments. In spite of higher exposure to ritonavir with 100 mg, atazanavir exposure was equivalent; the lipid profile was better under the lower booster dose (50 mg).

Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia

Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia

Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

Lopinavir/ritonavir (Kaletra) is first-line therapy for pediatric HIV infection. In clinical practice, Kaletra tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children. This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had 2 separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets. PK blood samples were drawn at 0 (predose), 1, 2, 4, 6, 8, and 12 hours postdose. Lopinavir and ritonavir plasma concentrations measured by high-performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance. Wilcoxon signed-rank tests compared PK values between crushed and whole tablets. Twelve children, median age of 13 years (10-16 years), took 550/138 mg·m(-2) per day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC after crushed and whole tablets were 92 mg·hr·L(-1) and 144 mg·hr·L(-1), respectively, with an AUC ratio of 0.55 (P = 0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg·hr·L(-1) and 13.3 mg·hr·L(-1), respectively, with an AUC ratio of 0.53 (P = 0.006). Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.

Primaquine decreased plasma concentration of ritonavir: single- and repeated-dose study in Sprague Dawley rats

Background: The present study was aimed to explore the effects of ritonavir and primaquine combination given as a singledose or repeated-dose compared to ritonavir alone on ritonavir plasma concentration in the rats. Methods: In single-dose study, 30 male Spraque Dawley rats were randomly allocated to receive ritonavir 20 mg/kg BW or ritonavir 20 mg/kg BW + primaquine 1.2 mg/kg BW or ritonavir 20 mg/kg BW + ketokonazole 10 mg/kg BW. Ketokonazole was used as positive control of ritonavir metabolism inhibitor. In the repeated-dose study, thirty Spraque Dawley male rats were randomly allocated to receive ritonavir 20 mg/kg BW/day or ritonavir 20 mg/kg BW/day + primaquine 1.2 mg/kg BW/day or ritonavir 20 mg/kg BW/day + rifampicin 100 mg/kg BW/day. Rifampicin was used as a positive control of ritonavir metabolism inducer. Results: In the single-dose study, ketokonazole increased the area under the plasma concentration (AUC) of ritonavir (↑114.8%, p&lt; 0.05), while primaquine tended to decrease the AUC of ritonavir (↓32.6%, p&gt; 0.05). Repeated-dose study showed that rifampicin decreases the AUC of ritonavir (↓42.8%, p&lt; 0.001), and primaquine decreased the AUC of ritonavir plasma concentration (↓46.6%, p&lt; 0.001). Conclusion: Concomitant administration of primaquine and ritonavir decreases the AUC of ritonavir. This effect may result in the insufficient concentration of ritonavir as anti-HIV, which may lead to treatment failure with ritonavir. (Med J Indones 2011; 20:190-4)

The Lopinavir/Ritonavir-Associated Rise in Lipids is not Related to Lopinavir or Ritonavir Plasma Concentration

The relationship between lopinavir plasma concentration and the magnitude of lipid elevation after initiation of lopinavir/ritonavir-containing antiretroviral therapy is unclear. The aim of this study was to determine the relationship between drug concentration and lipid changes in two patient cohorts. First, we analysed, in an outpatient cohort, the correlation between percentage lipid changes and lopinavir concentration, measured at least 2 weeks or more after initiation of lopinavir/ritonavir. Second, we analysed the correlation between lipid changes and lopinavir and ritonavir plasma concentrations in antiretroviral-naive patients enrolled in a trial comparing nevirapine plus lopinavir/ritonavir (533/133 mg twice daily) with zidovudine/lamivudine plus lopinavir/ritonavir (400/100 mg twice daily). In 82 outpatients with 215 lopinavir plasma measurements, we found no significant correlations between lopinavir concentration and changes in lipids a median of 522 days after lopinavir/ritonavir initiation in univariable regression analyses, nor in multivariable analyses adjusting for potential confounders. In 40 trial samples collected 24 months after treatment initiation, the mean (95% CI) percentage increase in low-density lipoprotein cholesterol (LDLc) was significantly greater in the nevirapine/lopinavir/ritonavir group (29.4% [16.8-43.3]) than in the zidovudine/lamivudine/lopinavir/ritonavir group (6.8% [-7.3-23.1]; P=0.03). However, the percentage LDLc change did not correlate with lopinavir or ritonavir concentration ratios (r=-0.25; P=0.17 and r=-0.06; P=0.75). Adding lopinavir or ritonavir concentrations into the multivariable regression analyses did not change the relation between LDLc change and randomized treatment. Neither in an HIV outpatient clinic cohort nor in a trial comparing two lopinavir/ritonavir-containing therapies did we find any relation between changes in lipids, and lopinavir and ritonavir concentration, after initiating lopinavir/ritonavir-containing treatment.

Clinical Evaluation of The Determination of Plasma Concentrations of Darunavir, Etravirine, Raltegravir and Ritonavir in Dried Blood Spot Samples

Measurement of drug levels in plasma is currently the gold standard for pharmacological studies. However, venous sampling is not feasible in some populations (e.g., neonates) or may be difficult in certain situations, such as nonhospital-based settings. Dried blood spots (DBS) can be obtained by a simple fingerprick and the subsequent collection of blood on a filter card, allowing patient-friendly sample collection in non-hospital-based settings. Despite these advantages, thus far no clinical evaluation has been performed for the use of DBS concentrations as surrogates for plasma levels. Our purpose was to clinically evaluate DBS sampling for the determination of plasma concentrations for the novel antiretroviral drugs etravirine, darunavir/ritonavir and raltegravir. DBS concentrations were measured in 11 HIV-infected patients using LC-MS/MS. DBS concentrations were proportional to plasma concentrations. All drug concentrations were higher in DBS than in plasma samples. The plasma:DBS ratio and the respective relative standard error of estimate (RSE) of darunavir, etravirine, raltegravir and ritonavir were 0.632 (4.97% RSE), 0.523 (4.84% RSE), 0.617 (14.9% RSE) and 0.592 (2.99% RSE), respectively. Hematocrit did not explain variability in our study. DBS are reproducibly correlated to plasma levels and can be used for monitoring antiretroviral drug exposure in HIV-infected patients.