O125 Impact of efavirenz and nevirapine on pharmacokinetics of lopinavir/ritonavir as tablets and capsules in African patients (original) (raw)
Antimicrobial Agents and Chemotherapy, 2010
/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n ؍ 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n ؍ 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n ؍ 20), nevirapine (n ؍ 18), and no NNRTI (n ؍ 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC 0-12 ) was 110.1 (34%) g ⅐ h/liter. For efavirenz, the geometric mean lopinavir AUC 0-12 (%CV) values were 91.8 g ⅐ h/liter (58%), 65.7 g ⅐ h/liter (39%), and 54.0 g ⅐ h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P ؍ 0.002) and 0.82 (90% CI, 0.68 to 0.99; P ؍ 0.09),
Antimicrobial Agents and Chemotherapy, 2011
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.
European Journal of Clinical Pharmacology, 2005
Objective: The influence of nevirapine (NVP) on lopinavir (LPV) pharmacokinetics was investigated by a population analysis based on a non-linear mixedeffect modelling method. Methods: In this analysis, 95 HIV-1 infected patients were studied [52 treated with LPV/ritonavir (400/100 mg twice a day) plus nucleoside reverse transcriptase inhibitors (group A), 22 patients treated with LPV/ritonavir (533.3/133.3 mg twice a day) plus NVP (group B) and 21 patients treated with LPV/ritonavir (400/ 100 mg twice a day) plus NVP (group C)]. Results: The apparent clearance of LPV [mean±SD: 4.56±3.94 l h À1 (group A) versus 7.14±1.77 l h À1 (group B) versus 7.74±1.45 l h À1 (group C)] was significantly (P <0.001) increased by the presence of NVP in the antiretroviral regimen and the mean trough plasma concentration of LPV was reduced in group C relative to group A [mean±SD: 2.23±1.35 mg/l versus 5.29±2.19 mg/l (P < 0.001)]. Conclusion: These results suggest an induction of LPV metabolism by NVP.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2012
We assessed pharmacokinetic (PK) parameters of reduced dose lopinavir/ritonavir (LPV/r) and compared generic and branded tablets. Twenty HIV-infected patients using protease inhibitors with HIV RNA ,50 copies per milliliter were randomized to generic or branded LPV/r 200/50mg twice daily (BID). At week 2, PK-sampling was performed. Patients crossed over to the other arm until week 12, with another PK-sampling at week 4. Subtherapeutic lopinavir concentrations were observed in 10/40 samples. PK parameters were comparable between branded and generic tablets. All patients remained virologically suppressed at week 12. In conclusion, LPV/r 200/50mg BID does not lead to adequate lopinavir plasma concentrations. Generic and branded LPV/r have comparable PK-parameters.
Journal of Antimicrobial Chemotherapy, 2012
Objectives: To evaluate the pharmacokinetic profile of ritonavir-boosted lopinavir in HIV-infected patients during rifabutin-based anti-mycobacterial therapy. Patients and methods: A longitudinal, cross-over pharmacokinetic evaluation of lopinavir with and without rifabutin in HIV-infected subjects with mycobacterial disease was done. All received lopinavir/ritonavir (400/100 mg twice a day)+ an adjusted rifabutin dose of 150 mg every other day. Twelve-hour lopinavir pharmacokinetic sampling occurred at 2 weeks (T1) and 6 weeks (T2) after starting combined therapy and 10 weeks after completion of adjusted rifabutin (T3). Plasma was assayed using an HPLC method; lopinavir plasma concentration-time data were analysed using non-compartmental methods. Results: In 10 patients with complete lopinavir curves at T1, T2 and T3 pharmacokinetic values were, respectively: AUC 0-12 , 187.5, 161.8 and 121.1 mg. h/mL; C trough , 13.2, 10.0 and 7.7 mg/mL; C max , 18.7, 15.9 and 13.3 mg/mL; and apparent oral clearance (CL/F), 0.035, 0.037 and 0.045 L/h/kg. Lopinavir C trough and AUC 0-12 were significantly higher at T1 compared with T3 while CL/F remained unchanged throughout. Combined treatment was well tolerated and none of the patients experienced moderate to severe lopinavir-related adverse events. Conclusions: Lopinavir serum concentrations are not reduced when the drug is administered together with an adjusted dose of 150 mg of rifabutin every other day.
Therapeutic Drug Monitoring, 2005
The influence of saquinavir hard-gel capsules on lopinavir pharmacokinetic parameters was investigated using a population approach. Forty-nine patients infected with human immunodeficiency virus type 1 and treated with lopinavir/ritonavir, nucleoside/nucleotide reverse transcriptase inhibitors plus saquinavir (group A), and 118 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (group B) were included in the study. No significant relationship was established between the presence or the daily dosage of saquinavir in the treatment and lopinavir population pharmacokinetic parameters. The values (mean 6 standard deviation) of the individual apparent clearance (5.0 6 1.8 vs. 5.0 6 3.2 L/h), volume of distribution (66.6 6 1.6 vs. 66.8 6 1.9 L), absorption rate constant (0.37 6 0.01 vs. 0.37 6 0.03 hours 21), and trough plasma concentration (5.5 6 2.3 vs. 5.3 6 1.9 mg/L) of lopinavir are not significantly different between groups A and B. This lack of influence of saquinavir on lopinavir pharmacokinetics makes the use of this combination in salvage therapy easier.
Pharmacokinetic evidence for the induction of lopinavir metabolism by efavirenz
British Journal of Clinical Pharmacology, 2005
Aims The influence of efavirenz on lopinavir pharmacokinetics was investigated using a population approach. Methods Forty-five HIV patients treated with lopinavir/ritonavir plus efavirenz (A) and 24 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (B) were studied. Results A relationship (P < 0.01) was established between the elimination rate constant of lopinavir (k 10) and treatment with efavirenz. Mean k 10 was higher in group A than in group B (0.3838 vs 0.2810 h-1) (P < 0.001, 95% confidence interval for difference between means 0.1004, 0.1052). Conclusions These results suggest that lopinavir metabolism is induced by efavirenz.
Plasma concentrations of generic lopinavir/ritonavir in HIV type-1-infected individuals
Antiviral Therapy, 2009
Background Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation. Methods In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (Cmin) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra® soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann–Whitney U test was used to compare the groups. Results A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of ...
Annals of Clinical Microbiology and Antimicrobials, 2020
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 Cmaxand Tmaxwere respectiv...
Pharmacokinetics of Adjusted-Dose Lopinavir-Ritonavir Combined with Rifampin in Healthy Volunteers
Antimicrobial Agents and Chemotherapy, 2004
Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (C max ) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (n ؍ 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (n ؍ 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean C max of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusteddose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.
Population Pharmacokinetics of Lopinavir/Ritonavir (Kaletra) in HIV-Infected Patients
Therapeutic Drug Monitoring, 2011
Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization (WHO) as first-line treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from six pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel-capsule, liquid, meltextrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3) with a one compartment semi-physiologic model. Lopinavir clearance was described by hepatic plasma flow (QHP) times hepatic extraction (EH), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70) 1.0 . Bioavailability was assessed separately as a function of hepatic extraction (FH) and the fraction absorbed from the GI tract (FABS). The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current WHO weight band dosing recommendations demonstrated that participants younger than 6 months of age had lower AUC (94.8 vs >107.4 mcg•hr/mL) and Cmin (5.0 vs > 7.1 mcg/mL) values compared to older children and adults. Although WHO dosing recommendations include a larger dosage (mg/m 2 ) in infants to account for higher apparent clearance (CL/F), they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.
Antimicrobial Agents and Chemotherapy, 2004
Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), 85.1 g/ml ⅐ h; maximum concentration of drug in serum (C max ), 10.0 g/ml; trough concentration of drug in serum (C trough ), 7.3 g/ml; and minimum concentration of drug in serum (C min ), 5.5 g/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC 0-12 , 22.9 g/ml ⅐ h; C max , 2.9 g/ml; C trough , 1.6 g/ml; and C min , 1.4 g/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitorbased antiretroviral regimen for patients with several prior virologic failures.
The Journal of Clinical Pharmacology, 2018
Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization (WHO) as firstline treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from six pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2005
Background: Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied.
Journal of Antimicrobial Chemotherapy, 2011
To characterize the pharmacokinetics and inhibitory quotient (IQ) of atazanavir/ritonavir-and lopinavir/ritonavir-based regimens in HIV-infected, treatment-naive patients. Methods: The CASTLE Study was a 96 week randomized study comparing 300 mg of atazanavir once daily with 400 mg of lopinavir twice daily, each with low-dose ritonavir (100 mg) plus tenofovir disoproxil fumarate/ emtricitabine in HIV-infected, treatment-naive patients. A subset of patients participated in an intensive pharmacokinetic evaluation of the atazanavir regimen (n¼ 18) and the lopinavir regimen (n¼21) at week 4. (ClinicalTrials.gov NCT00272779) Results: Atazanavir geometric mean (CV%) C max , C min and AUC over the dosing interval were 2897 (46) ng/mL, 526 (57) ng/mL and 28605 (46) ng. h/mL, respectively, and for lopinavir they were 10655 (51) ng/mL, 5944 (68) ng/mL and 90946 (59) ng. h/mL, respectively. The baseline protein binding-adjusted 90% effective concentration (PBA-EC 90) was 16 (44) ng/mL for atazanavir and 173 (44) ng/mL for lopinavir. The median IQ (min, max), calculated as the ratio of C min to individual baseline PBA-EC 90 , was 35 (4, 77) for atazanavir and 34 (11, 129) for lopinavir. The C max for ritonavir was 46% higher, while AUC 0-24 and C min were 16% and 72% lower in the atazanavir regimen compared with the lopinavir regimen. Tenofovir exposures were similar with both treatments. Conclusions: Atazanavir (300 mg once daily) and lopinavir (400 mg twice daily), each with low-dose ritonavir, achieved similar IQs in HIV-infected, treatment-naive patients. These results are supportive of the main clinical finding of the CASTLE Study, that the atazanavir/ritonavir-based regimen is non-inferior in antiviral efficacy to the lopinavir/ritonavir-based regimen in antiretroviral-naive subjects.
Journal of Pharmacological Sciences, 2020
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