The Effect of Acid Reduction With a Proton Pump Inhibitor on the Pharmacokinetics of Lopinavir or Ritonavir in HIV‐Infected Patients on Lopinavir/Ritonavir‐Based Therapy

Overton, Edgar Turner; Tschampa, Jean M.; Klebert, Michael; Royal, Mike A.; Rodriguez, Mark; Spitz, Teresa; Kim, Ge Youl; Mondy, Kristin; Acosta, Edward P.

doi:10.1177/0091270009357431

Cited by 7 publications

(5 citation statements)

References 19 publications

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“…The estimated clearance of LPV t from the final model in this work is 4.73 L/h, compared to prior CL/F values ranging from 3.2 to 5.22 L/h [25-29]. Distribution volume for LPV t has been reported ranging from 42.6 to 61.6 L, [5, 25, 27] which is similar to our result of 55.7 L. The LPV t absorption rate (K aLPVt ) shown in Table 2 is 0.325 h -1 , which is also within the previously reported range of 0.267 to 0.564 h -1 [5, 26].…”

Section: Discussionmentioning

confidence: 96%

Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

et al. 2013

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Background Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI) based regimen to treat HIV-infection. As with all PIs, the trough concentration (Ctrough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein (AAG) and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Methods Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. Results LPVt typical value of clearance (CLLPVt/F) was 4.73 L/h and distribution volume (VLPVt/F) was 55.7 L. Clearance (CLLPVf/F) and distibution volume (Vf/F) for LPVf were 596 L/h and 6370 L, respectively. Virion clearance rate was 0.0350 h-1. Simulated LPVLPVt Ctrough at 90% (EC90) and 95% (EC95) maximum response were 316 and 726 ng/mL, respectively. Conclusion The pharmacokinetic/pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modeling and simulation approach could be used as a surrogate assessment of ARV where adequate early phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.

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Section: Discussionmentioning

confidence: 96%

Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

et al. 2013

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“…A thorough review of the literature since 2006 has yielded additional PPI drug interactions modulated by gastric pH, such as those reported with mycophenolate mofetil [13, 14, 16], the instability of PPIs themselves at low pH [17], and the altered pharmacokinetics of several protease inhibitors (including atazanavir [19], nelfinavir [20], raltegravir [21], ritonavir [22–24], and indinavir [25]). There are, however, a few new CYP-mediated drug interaction studies, with the most notable being the new data on dexlansoprazole and data for interactions between some PPIs and clopidogrel.…”

Section: Discussionmentioning

confidence: 99%

“…Ritonavir itself has better solubility at a lower pH, boosts other protease inhibitors by inhibiting CYP3A4, is metabolised by CYP3A4 (similar to PPIs) and is a substrate and inhibitor of P-glycoprotein [22–24]. …”

Section: Mechanisms Involved In Proton Pump Inhibitor Drug Interactionsmentioning

confidence: 99%

“…Total and maximum exposure of the non-ionizable lopinavir and ritonavir at steady state were both increased by about 25 % when administered with omeprazole, without obvious changes in the elimination [22]. These findings were explained by an increase in exposure to ritonavir resulting from inhibition of P-glycoprotein by omeprazole and a subsequent stronger inhibitory effect on CYP3A4 by ritonavir.…”

Section: Mechanisms Involved In Proton Pump Inhibitor Drug Interactionsmentioning

confidence: 99%

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Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

2014

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Proton pump inhibitors (PPIs) are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. These drug–drug interactions have been previously reviewed. However, the current knowledge is likely to have advanced, so a thorough review of the literature published since 2006 was conducted. This identified new studies of drug interactions that are modulated by gastric pH. These studies showed the effect of a PPI-induced increase in intragastric pH on mycophenolate mofetil pharmacokinetics, which were characterised by a decrease in the maximum exposure and availability of mycophenolic acid, at least at early time points. Post-2006 data were also available outlining the altered pharmacokinetics of protease inhibitors with concomitant PPI exposure. New data for the more recently marketed dexlansoprazole suggest it has no impact on the pharmacokinetics of diazepam, phenytoin, theophylline and warfarin. The CYP2C19-mediated interaction that seems to exist between clopidogrel and omeprazole or esomeprazole has been shown to be clinically important in research published since the 2006 review; this effect is not seen as a class effect of PPIs. Finally, data suggest that coadministration of PPIs with methotrexate may affect methotrexate pharmacokinetics, although the mechanism of interaction is not well understood. As was shown in the previous review, individual PPIs differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole sodium (pantoprazole-Na) have been studied most extensively. Several studies have shown that omeprazole carries a considerable potential for drug interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4. In contrast, pantoprazole-Na appears to have lower potential for interactions with other medications. Lansoprazole and rabeprazole also seem to have a weaker potential for interactions than omeprazole, although their interaction profiles, along with those of esomeprazole and dexlansoprazole, have been less extensively investigated. Only a few drug interactions involving PPIs are of clinical significance. Nonetheless, the potential for drug interactions should be considered when choosing a PPI to manage gastric acid-related disorders. This is particularly relevant for elderly patients taking multiple medications, or for those receiving a concomitant medication with a narrow therapeutic index.

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“…Antiretroviral agents with a pH‐dependent solubility and gastric absorption such as atazanavir showed significant decreases of plasma concentrations when co‐administered with acid‐reducing agents, despite boosting with low‐dose ritonavir [6, 7]. No clinically significant interaction was observed when omeprazole or ranitidine was co‐administered with boosted indinavir [8], fosamprenavir [6, 9], darunavir [10], tipranavir [11] or lopinavir [12–14]. Conversely, exposure to boosted saquinavir increased substantially when co‐administered with omeprazole 40 mg q.d., regardless of whether the drugs were administered simultaneously or 2 h apart [15, 16].…”

Section: Introductionmentioning

confidence: 99%

A pharmacokinetic study of etravirine (TMC125) co‐administered with ranitidine and omeprazole in HIV–negative volunteers

Schöller-Gyüre¹,

Kakuda²,

Smedt³

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-drug interactions with acid-suppressing agents were previously described with several other antiretroviral drugs.• Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor, metabolized by CYP3A and CYP2C enzymes with demonstrated efficacy in treatment-experienced HIV-infected patients.• The effect of acid-suppressing agents on the pharmacokinetics of etravirine was unknown. WHAT THIS STUDY ADDS• No clinically relevant effect was shown on the pharmacokinetics of etravirine when co-administered with ranitidine or omeprazole, drugs that increase gastric pH.• A drug-drug interaction due to CYP2C19 inhibition by omeprazole has been identified.• Etravirine can be co-administered with proton pump inhibitors and H2 antagonists without dose adjustments. AimsEtravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H2-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. MethodsIn an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. ResultsNineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUClast and Cmax were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. ConclusionsRanitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H2 antagonists without dose adjustments.

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The Effect of Acid Reduction With a Proton Pump Inhibitor on the Pharmacokinetics of Lopinavir or Ritonavir in HIV‐Infected Patients on Lopinavir/Ritonavir‐Based Therapy

Cited by 7 publications

References 19 publications

Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update

A pharmacokinetic study of etravirine (TMC125) co‐administered with ranitidine and omeprazole in HIV–negative volunteers

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