Drug-Drug Interactions Between Protease Inhibitors and Statins and Proton Pump Inhibitors: a Systematic Review Charles Orido, Samantha Mckinnon and DR

Drug-drug interaction between Protease inhibitors and statins and Proton pump inhibitors

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Authors Orido, Charles; McKinnon, Samantha

Publisher The University of Arizona.

Download date 28/09/2021 12:23:53

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Link to Item http://hdl.handle.net/10150/636245 Drug-Drug Interactions between Protease Inhibitors and Statins and proton Pump inhibitors: A Systematic Review Charles Orido, Samantha McKinnon and DR. Dan Malone PharmD University of Arizona College of Pharmacy

BACKGROUND RESULTS RESULTS • . Protease inhibitors (PIs) are HIV and Hepatitis C drugs that block a protease from Characteristics and Outcomes of Included Studies making protein by competitive inhibition. The are CYP3A4 inhibitors. • Recent studies suggest that when PIs are given with Statins (primarily metabolized by Table 1 Studies of simvastatin and Protease inhibitors Fig. 1: Chemical structures of HMG-CoA reductase inhibitors (statins). The lactone CYP3A4) especially Simvastatin and Lovastatin, they increases the AUC and Cmax of Reference Design Patient n Reference Protease Inhibitor Statin AUC Cmax Comments statins which leads to serious adverse events and even death. population regimen ring is underlined in green and the efficacious acid moiety is underlined in red. Hsyu et al. 2001 Open-label, sequential, Healthy 32 Simvastatin 20 mg Nelfinavir 1250 mg Simvastatin co-administered ↑ 505 % ↑517 % ADE: • Atazanavir (ATV) is a potent, well-tolerated, once daily, HIV protease Inhibitor [1] multiple-dose, single BID with NFV after 14 days on Diarrhea center study Simvastatin alone Rash extensively studied in naïve and experienced patients. Migraine headache ↓Fasting cholesterol • ATV exhibits pH-dependent solubility, previous data have indicated that ATV ↓LDL bioavailability is sensitive to gastric PH. Is a moderate Inhibitor of CYP2C19 in vitro Fichtenbaum et al Randomized phase 1, HIV Serone- 67 Simvastatin 40 Atazanavir/ Simvastatin 40mg/day ↑59% ↑328% ADE: 2002 open label, multiple gative mg/day ritonavir 300 mg BID administered with RTV after 14 Diarrhea • Proton Pump Inhibitors (PPIs) are primarily metabolized by CYP2C19, suppresses acid dose Sequinavir 400 days or simvastatin alone GI upset mg/day BID Simvastatin 40 mg/day Concentration increased secretion and increases gastric PH. administered with SQV after 14 30-fold days of simvastatin alone.

Methaneethorn et Open-label, sequential, Healthy Simvastatin 20 Nelfinavir Simvastatin co-administered Concentration Increased al 2014 multiple dose, single mg/day with NFV after 14 days on 6-fold. OBJECTIVE center Simvastatin alone Hare et al 2002 Case report HIV 1(70-year-old Simvastatin 80 mg Nelfinavir 750 mg TID Simvastatin concurrent with Muscle weakness The purpose of this article is to provide a systematic review of the pharmacokinetic and white male /day Nelfinavir Diarrhea Acute renal failure clinical data on drug-drug interactions between protease inhibitors (PIs) and statins, Oliguria Metabolic acidosis atazanavir and proton pump inhibitors (PPIs) and discuss their clinical relevance. Elevated troponin-1 Elevated creatine kinase Rhabdomyolysis Death METHODS Ginelle et al 2007 Case report HIV 1(72-year-old Simvastatin 80 Atazanavir 400 mg at Simvastatin concurrent with Weakness white male mg/day bedtime Atazanavir 27days and Fatigue Amiodarone 400 mg amiodarone for 7 days Muscle pain Search Strategy & Study Selection daily for 7 days then Increased creatine kinase 200 mg daily. Dark orange urine Oliguric renal failure • A literature search was performed using Medline, EMBASE, and google scholar, Cheng et al 2002 Case report HIV 1(51-year-old Simvastatin 20 Indinavir 800 mg BID Simvastatin concurrent with Elevated aspartate transaminase, LDH, abstracts from 1970 to 2019 of major conferences were searched and currently white woman mg/day Ritonavir 100 mg BID Indinavir and ritonavir. Ritonavir alanine transaminase. added 1 week before admission Rhabdomyolysis. available FDA drug information package inserts was examined. • Articles were eligible for inclusion if they were: AM, morning; ATV, atazanavir; AUC, area under the curve; bid, twice a day; Cmax, maximum concentration; CO, cross-over; d, day(s); DB, double-blind; DRV, darunavir; FPV, fosamprenavir; DISCUSSION & CONCLUSION h, hour; IDV, indinavir; LPV/r, lopinavir/ritonavir; n, number of participants; OL, open label: PM, evening; PG, parallel group; PK, pharmacokinetics; qd, once a day; R, randomized; TV or r, ritonavir; SQV, saquinavir; BID, two times a day; TPV, tipranavir. 1. Published in English between January 1970 and October 2019 • Protease Inhibitors increased the AUC and Cmax of simvastatin by approximately 2. Healthy individuals or persons with HIV/AIDS of any ages Table 2Studies of Proton Pump Inhibitors and Protease Inhibitors 500% and 517 respectively. 3. Reported any incidence pharmacokinetic or pharmacodynamics • Therefore, simvastatin and Lovastatin are not recommended co-administration with Reference Design Patient n Reference regimen Protease Inhibitor Statin AUC Cmax Comments population a Protease Inhibitors. Zhu et al 2011 Cohort Healthy 56 Atazanavir 400mg qd ATV 400 mg qd OMP 20 mg QAM 12 h ↓38 % • Two independent authors screened titles and abstracts, and then extracted data ATV/r 300/100 mg before ATV/r ↓42 % • Other statins can be used like atorvastatin, rosuvastatin and pravastatin which is qd OMP 20 mg QAM 1 h before ↓37 % following a full-text review of included articles ATV/r 400/100 mg ATV/r the main statin recommended. qd OMP 20 mg 12 h after ATV/r • Atazanavir can be administered with PPIs but if possible, change of an acid Agarwala et al. Randomized, parallel Healthy 48 Atazanavir/ ATV/r 300/100 mg OMP 40 mg qd, 2 h before ↓76% ↓72% 2005 group, open label, ritonavir 300/100 mg qd ATV/r reducing agent may be warranted. multiple doses. qd ATV/r 300/100 mg OMP 40 mg qd, 2 h before qd1cola ATV/r ↓70% ↓66% • Providers should keep a close eye to those patients taking atazanavir and PPIs Risk of Bias ATV/r 400/100 mg OMP 40 mg qd, 2 h before qd ATV/r and consider a change to H2RA. ↓61% ↓66% Instrument and data collection: Case reports were assessed using the called Drug Interaction Luber et al. 2006 Randomized, Cross Healthy 19 ATV/r 300/100 mg qd ATV/r 300/100 mg OMP 20 mg single dose . Probability Scale (DIPS) developed by Horn et. al. to evaluate the quality of DDI case Over, Open Label, AM qd Am PM multiple doses, ATV/r 300/100 mg OMP 20 mg qd PM reports. If the total DIPs score is >8 then it is suggestive of a (highly probable) drug interaction. qd ↓27% ↓33% AM REFERENCES Lower values of 5-8 probable of drug interaction, 2-4 possible of drug interaction, and <2 Tomilo et al. Cross Over, Open Healthy 9 ATV 400 mg single ATV 400 mg single LANS 60 mg qd x 2 ↓94% ↓91% Standard Lansoprazole dose is 30mg doubtful of drug interaction. 2006 Label, dose dose doses 1. Béïque, L, et al. “Interactions between Protease Inhibitors and Acid-Reducing Agents: a Systematic Review.” HIV Medicine, vol. 8, no. 6, 2007, Agarwala et al. R, PG, OL, multiple Healthy 48 ATV 400 mg qd ATV 400 mg qd OMP40 mg qd, 2 h before ↓94% ↓96% pp. 335–345., doi:10.1111/j.1468-1293.2007.00482. x. Accessed November 1028 2005 doses ATV 400 mg qd 1 ATV 2. Chastain, Daniel B., et al. “Evidence-Based Review of Statin Use in Patients with HIV on Antiretroviral Therapy.” Journal of Clinical & Study Selection Cola OMP 40 mg qd, 2h before Translational Endocrinology, vol. 8, 2017, pp. 6–14., doi: 10.1016/j.jcte.2017.01.004. Accessed November 2018 ATV/r 300/100 qd ATV ↓93% ↓94% 3. Hsyu, P.-H., et al. “Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Records Records Full-text OMP 40 mg qd, 2 h before Atorvastatin and Simvastatin.” Antimicrobial Agents and Chemotherapy, vol. 45, no. 12, 2001, pp. 3445–3450., doi:10.1128/aac.45.12.3445- Records Studies ATV/r ↓50% ↓73% 3450.2001. Accessed November 2018 identified after articles 4. Al, Fichtenbaum Et. “Pharmacokinetic Interactions between Protease Inhibitors and Statins in HIV Seronegative Volunteers.” Aids, vol. 17, no. after included in Klein et al. 2006 R, PG, OL, multiple Healthy 10 ATV/r 300/100 mg qd ATV/r 300/100 mg OMP 40 mg qd, 1.5 h 62 59 RTV AUC ↓ 16%, through duplicate assesse Supplement 4, 2003, pp. 109–110., doi:10.1097/00002030-200317004-00017. Accessed November 2018. inclusion systematic [//] doses qd before ATV/r Cmax and Cmin no change 5. Schmidt, G. A., et al. “Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin, Amiodarone, and database s d for Atazanavir.” The Journal of the American Board of Family Medicine, vol. 20, no. 4, 2007, pp. 411–416., doi:10.3122/jabfm.2007.04.060187. criteria review Faber et al 2016 Ranndomized, single- Healthy 8 Atazanavir/ atazanavir/ Rebeprazole 200 mg BID + ↓70% ↓35% searching removed eligibility Accessed November 2018 [//] dose, 3 period, Ritonavir 300/100 mg ritonavir 300/100 atazanavir/ritonavir 300/100 6. Agarwala S, Gray K, Eley T, Wang Y, Hughes E, Grasela D. Pharmacokinetic interaction between atazanavir and omeprazole in healthy crossover mg mg (n=34) (n=14) subjects. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, 24–27 July 2005 [Abstract study (n=246) (n=24) (n=24) WePe3.3C08]. The ‘multiple doses’ design indicates that all agents are given for multiple doses, except where otherwise specified. 7. Klein C, Chiu YL, Cai Y et al. Lack of effect of acid reducing agents on the pharmacokinetics of lopinavir/ritonavir tablet formulation. 13th AM, morning; ATV, atazanavir; AUC, area under the curve; bid, twice a day; Cmax, maximum concentration; CO, cross-over; d, day(s); DB, double-blind; DRV, darunavir; ESO, esomeprazole; FPV, fosamprenavir; h, hour; IDV, Conference on Retroviruses and Opportunistic Infections. Denver, CO, 5–8 February 2006 [Abstract 578]. Disclosure: Authors have nothing to disclose. For more information, contact Charles Orido, indinavir; LANS, lansoprazole; LPV/r, lopinavir/ritonavir; n, number of participants; OL, open label; OMP, omeprazole; PM, evening; PC, placebo-controlled; PG, parallel group; PK, pharmacokinetics; qd, once a day; R, 8. Luber, Ad, et al. “Steady-State Pharmacokinetics of Once-Daily Fosamprenavir/Ritonavir and Atazanavir/Ritonavir Alone and in Combination Samantha McKinnon and DR. Dan Malone at [email protected] randomized; TV or r, ritonavir; SQV, saquinavir; BID, two times a day; TPV, tipranavir. with 20 Mg Omeprazole in Healthy Volunteers*.” HIV Medicine, vol. 8, no. 7, 2007, pp. 457–464., doi:10.1111/j.1468-1293.2007.00496. x.