O125 Impact of efavirenz and nevirapine on pharmacokinetics of lopinavir/ritonavir as tablets and capsules in African patients (original) (raw)
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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.
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 (C min) 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 intolerance. The median (interquartile range) lopinavir C min was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C min levels was found between Kaletra®, and the generic product (P=0.224). By contrast, the C min of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients. Conclusions: The generic lopinavir/ritonavir tablet showed C min plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle-and low-income countries. The availability of generic products is an important factor in the global scale-up of antiretroviral treatment (ART) for HIV-infected patients [1]. Data collected by the Global Price Reporting Mechanism showed that 96% of generic antiretrovirals (ARVs) used were for first-line ART, with generic products accounting for only 7% of all second-line ARVs being used [2,3]. At present, approximately 97% of adults and children treated with ARVs in low-and middle-income countries are receiving first-line therapy [4]. It is estimated, however, that 6-10% of the patients per year will need second-line ART because of first-line treatment failure [5]. The average price of second-line regimens can cost up to 5× more compared with the first-line regimens [3]. This is not only a result of higher production costs, but also because of the lack of competition with limited World Health Organization (WHO) pre-qualified generic second-line ARVs [4]. Lopinavir/ritonavir is the leading protease inhibitor used for second-line ART in patients failing first-line non-nucleoside reverse transcriptase inhibitor-based regimens. It has advantages over other ritonavirboosted protease inhibitors for its combined lopinavir and ritonavir formulation in addition to its heat
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.