Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir

Stephan, Christoph; Hentig, Nils von; Kourbeti, Irene S.; Dauer, Brenda; Mösch, Manfred; Lutz, Thomas; Klauke, Stephan; Harder, Sebastian; Kurowski, Michael; Staszewski, Schlomo

doi:10.1097/00002030-200402200-00017

Cited by 46 publications

(32 citation statements)

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“…Furthermore, exposure and maximum concentrations were reduced by 14% and 17%, respectively, when given with darunavir (800 mg-100 mg once daily) (15) and between 70% and 90% in the presence of different tipranavir doses (2a). One study previously documented approximately 50% lower ritonavir concentrations with lopinavir (14), and another study observed significantly lower ritonavir concentrations in the presence of lopinavir (400 mg-100 mg twice daily) than in the presence of atazanavir (300 mg-100 mg once daily). In addition, the ritonavir AUC 0-24 and C max were only 26% and 43% higher, respectively, when given once daily with lopinavir than with atazanavir despite doubling the daily dose (lopinavir-ritonavir at 800 mg-200 mg once daily versus atazanavir-ritonavir at 300 mg-100 mg once daily) (4).…”

Section: Discussionmentioning

confidence: 99%

“…Lopinavir concentrations were significantly increased in the presence of ritonavir and were correlated with the ritonavir dose (i.e., higher ritonavir doses produce higher lopinavir concentrations) (8). Moreover, ritonavir plasma concentrations were reduced in the presence of lopinavir; for example, ritonavir exposure was 50% lower with coadministration with lopinavir (400 mg-100 mg twice daily) than with coadministration with saquinavir (1,000 mg-100 mg twice daily) (14). Following a previously reported meta-analysis of 5 lopinavir-ritonavir pharmacokinetic studies, a dose of 200 mg-150 mg twice daily (1 lopinavir-ritonavir tablet plus 1 ritonavir tablet) was determined to exhibit exposures and minimum concentrations similar to those of the standard 400-mg-100-mg twice-daily dose based on geometric mean ratios (GMRs) and 95% confidence intervals (CIs) (8).…”

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Sequential Population Pharmacokinetic Modeling of Lopinavir and Ritonavir in Healthy Volunteers and Assessment of Different Dosing Strategies

Dickinson

Boffito²,

Back

et al. 2011

Antimicrob Agents Chemother

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Nonlinear mixed-effects modeling was applied to explore the relationship between lopinavir and ritonavir concentrations over 72 h following drug cessation and also to assess other lopinavir and ritonavir dosing strategies compared to the standard 400-mg-100-mg twice-daily dose. Data from 16 healthy volunteers were included. Possible covariates influencing lopinavir and ritonavir pharmacokinetics were also assessed. Data were modeled first separately and then together by using individually predicted ritonavir pharmacokinetic parameters in the final lopinavir model. The model was evaluated by means of a visual predictive check and external validation. A maximum-effect model in which ritonavir inhibited the elimination of lopinavir best described the relationship between ritonavir concentrations and lopinavir clearance (CL/F). A ritonavir concentration of 0.06 mg/liter was associated with a 50% maximum inhibition of the lopinavir CL/F. The population prediction of the lopinavir CL/F in the absence of ritonavir was 21.6 liters/h (relative standard error, 14.0%), and the apparent volume of distribution and absorption rate constant were 55.3 liters (relative standard error, 10.2%) and 0.57 h ؊1 (relative standard error, 0.39%), respectively. Overall, 92% and 94% of the observed concentrations were encompassed by the 95% prediction intervals for lopinavir and ritonavir, respectively, which is indicative of an adequate model. Predictions of concentrations from an external data set (HIV infected) (n ‫؍‬ 12) satisfied predictive performance criteria. Simulated lopinavir exposures at lopinavirritonavir doses of 200 mg-150 mg and 200 mg-50 mg twice daily were 38% and 65% lower, respectively, than that of the standard dose. The model allows a better understanding of the interaction between lopinavir and ritonavir and may allow a better prediction of lopinavir concentrations and assessments of different dosing strategies.Coformulated lopinavir-ritonavir (Kaletra; Abbott Laboratories, Chicago, IL) has demonstrated durable treatment efficacy in HIV-infected treatment-naïve and -experienced patients (12). It is approved for use at doses of 400 mg-100 mg twice daily and additionally at 800 mg-200 mg once daily for treatment-naïve patients in Europe and the United States (1, 2). Initially, lopinavir-ritonavir was available as soft-gel capsules, which required refrigerated storage and administration with food. However, a tablet formulation has been developed, with a diminished food effect, reduced variability compared to that of soft-gel capsules, and increased heat stability, therefore no longer needing refrigeration (9). Furthermore, data suggest a trend toward an increased bioavailability of the tablets (9).Hill et al. recently performed a systematic review of 17 dose-ranging pharmacokinetic studies involving ritonavirboosted protease inhibitors in order to assess the effects of ritonavir on different protease inhibitors and vice versa. Lopinavir concentrations were significantly increased in the presence of ritonavir and were c...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Sequential Population Pharmacokinetic Modeling of Lopinavir and Ritonavir in Healthy Volunteers and Assessment of Different Dosing Strategies

Dickinson

Boffito²,

Back

et al. 2011

Antimicrob Agents Chemother

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“…There was no CD4 cell count or viral load restriction included in this study. Patients completed a 24-h pharmacokinetic assessment according to a standardized therapeutic drug monitoring (TDM) protocol that is used for all outpatients [14]. Pharmacokinetic data were assessed from all patients who started on antiretroviral therapy (ART) containing atazanavir/ ritonavir as first-line therapy in June 2003 and participated in routine TDM procedures until June 2006 and who concomitantly were taking a methadone oral solution as opiate substitution therapy.…”

Section: Patientsmentioning

confidence: 99%

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Haberl

Moesch

Nisius

et al. 2009

Eur J Clin Pharmacol

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Objective The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n=12) or without (n=12) methadone co-administration. Methods Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C min , C max ), area under the concentration-time curve (AUC), and total clearance (CL total ) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity. Results The GM [90% confidence interval (CI)] of the atazanavir C min , C max , and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C min =315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR)=0.61, p=0.229]; C max =1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR=0.54, p=0.018); AUC=21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR=0.62, p=0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C max (r 2 =0.40, p=0.001) and AUC (r 2 =0.32, p=0.006). Ritonavir pharmacokinetics was similar between the groups with C min , C max , and AUC GMR of 1.01, 0.80, and 0.96, respectively. Conclusion The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.

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“…A nucleoside-free combination of lopinavir (LPV)-ritonavir (RTV) and ATV can be an alternative therapy regimen for human immunodeficiency virus type 1 (HIV-1)-infected patients who have no further options with nucleoside reverse transcriptase inhibitors (NRTI) due to toxicity or resistance, as previously shown for other protease inhibitor combinations (12,13,17). Both LPV and ATV are highly potent against HIV-1; i.e., they have a low in vivo 50% inhibitory concentration for wild-type HIV-1 replication (Kaletra package insert, Abbott Laboratories, Chicago, IL; Reyataz Product Information, Bristol Myers-Squibb Company, Princeton, NJ).…”

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confidence: 99%

“…Converse differences in the C min (geometric mean ratio, 2.40 [P ϭ 0.004]) of RTV were due to the different RTV dosing intervals in the two regimens. It has been shown before that plasma RTV concentrations were significantly decreased when the drug was taken as part of an LPV-RTV coformulation, but it was also reported that even very low plasma RTV concentrations sufficiently enhance the plasma concentrations of other HIV protease inhibitors (13), so that the mechanisms of the interaction between LPV and ATV remain unknown.…”

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confidence: 99%

Decrease of Atazanavir and Lopinavir Plasma Concentrations in a Boosted Double Human Immunodeficiency Virus Protease Inhibitor Salvage Regimen

Hentig

Kaykhin²,

Stephan³

et al. 2008

Antimicrob Agents Chemother

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The human immunodeficiency virus protease inhibitor combination of atazanavir (ATV)-lopinavir-ritonavir was reported to exhibit a mutual pharmacoenhancement of plasma lopinavir and ATV concentrations which may be beneficial for salvage patients. We identified 17 patients in our pharmacokinetic database taking this combination and found conflicting results. Plasma concentrations of both ATV and lopinavir were modestly, although not significantly, decreased when the drugs were coadministered. Therefore, patients should be selected carefully for this regimen and frequent clinical and therapeutic drug monitoring is strongly advised.

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Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir

Abstract: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.

Cited by 46 publications

References 10 publications

Sequential Population Pharmacokinetic Modeling of Lopinavir and Ritonavir in Healthy Volunteers and Assessment of Different Dosing Strategies

Sequential Population Pharmacokinetic Modeling of Lopinavir and Ritonavir in Healthy Volunteers and Assessment of Different Dosing Strategies

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Decrease of Atazanavir and Lopinavir Plasma Concentrations in a Boosted Double Human Immunodeficiency Virus Protease Inhibitor Salvage Regimen

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