sign in sign up
<<
Home , Indinavir, Simvastatin

Drug- between Protease inhibitors and and Proton pump inhibitors

Item Type text; Electronic Report

Authors Orido, Charles; McKinnon, Samantha

Publisher The University of Arizona.

Rights Copyright © is held by the author.

Download date 01/10/2021 01:48:07

Item License http://rightsstatements.org/vocab/InC/1.0/

Link to Item http://hdl.handle.net/10150/636245 Group 47 :Orido/Samantha 1

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

Course Title: PhPr 862 Date: April 3, 2019 Faculty Advisor: Dr. Dan Malone Students: Charles Orido, Samantha McKinnon Pharm.D. Candidates, Class of 2019

Group 47 :Orido/Samantha 2

Objective The purpose of this article is to provide a systematic review of the pharmacokinetic and clinical data on drug-drug interactions between

protease inhibitors (PIs) and statins, and proton pump inhibitors (PPIs)and their clinical relevance.

Methods

A literature search was performed using Medline, EMBASE and google scholar, abstracts from 1970 to 2019 of major conferences were searched and FDA drug information package inserts of the manufacturer of every currently available PI was looked at. All data was summarized and verified by at least two investigators.

Results

A total of 246 references were identified, 8 of which were studies of pharmacokinetic and pharmacodynamics interactions between , and protease inhibitors and an additional 7 articles that provided pharmacokinetic of proton pump inhibitors and

Atazanavir.

Conclusions

Protease inhibitors increases the AUC and Cmax of simvastatin by approximately 500% and 517% respectively. Therefore, simvastatin and

Lovastatin are not recommended for a co-administration with a protease inhibitor. Other statins such as and , can be used and are the main statins recommended. Atazanavir can be administered with PPIs but change of an acid reducing agent may be warranted, if possible. Providers should keep a close eye to those patients taking atazanavir and PPIs and consider a change to H2RA.

.

Keywords: Proton Pump Inhibitors, Simvastatin, Lovastatin, protease inhibitors, Group 47 :Orido/Samantha 3

INTRODUCTION

Granting that adverse drug events are not serious, some may cause death, hospitalization, or even serious injury. Statistics say drug adverse events are one of the leading causes of death around the world. Adverse events resulting from drug-drug interaction can and should be avoided. Drug-drug interactions (DDI) is defined as the modification of the effect of one drug (the object drug) by the prior concomitant administration of another (precipitant drug). Concomitant use of several drug in the presence of another is often necessary for achieving a set goal or in the case when a patient is suffering from more than one disease. Mechanism of drug interactions is and pharmacodynamics.

Pharmacokinetics involves the effect of a drug on another drug kinetics that include absorption, distribution, and .

Pharmacodynamics is related to the pharmacological activity of the interacting drugs e.g. synergism, antagonism and altered cellular transport effect on the receptor site.

According to UNAIDS they were approximately 36.7 million people worldwide living with HIV/AIDS at the end of 2016 [1,2]. An estimated 1.8 million individuals worldwide became newly infected with HIV in 2016 – about 5,000 new infections per day. Most children living in sub-Saharan Africa were infected by their HIV-positive mothers during , childbirth and/or . One million people died from AIDS-related illnesses in 2016, bringing the total number of people who have died from AIDS-related illnesses since the start of the epidemic to 35.0 million [1,2]. As of July 2017, 20.9 million people living with HIV have access to antiretroviral therapy (ART) globally, up from

15.8 million in June 2015, 7.5 million in 2010, and less than one million in 2000. On average a person living with HIV can be taking between 2 to

30 a day [1,2,3]. These high number of people accessing ART highlights that the risk of a DDI occurring is significant because the number of potential interactions increases as a function of the number of medications a patient is taking. HIV ART can also cause drug-drug interactions when used with other medications. Hence, it is imperative that pharmacists play an important role in detecting this interaction. These Group 47 :Orido/Samantha 4

interactions can cause death therefore, pharmacists should counsel their patients on the best practices, such as avoiding over the counter

and talking to their pharmacist or doctor first.

Protease inhibitors are drugs that block a protease from making protein by competitive inhibition. They are widely used to treat

HIV/AIDS and hepatitis C virus. Protease inhibitors selectively inhibits the HIV type 1 (HIV-1) protease , which is required for the processing of viral gag and gag-pol precursor polyproteins. The interruption of this latter step in the HIV life cycle prevents the efficient

processing of viral structural proteins, thus preventing the formation of an infectious and mature viral particle. These medications are commonly

used to treat HIV infection with a goal of suppressing the viral load, reducing morbidity, maximizing survival and restoring and maintaining

immunological function. Adverse drug reactions to protease inhibitors include , changes in PH, changes in the distribution of body

fat and an increase in and triglycerides. Changes in body distribution associated with protease inhibitors are the most serious side

effects associated with therapy and differ from drug to drug [7]. The metabolic disturbance of normal bodily functioning associated with protease

inhibitor therapy are the most problematic adverse events associated with therapy and vary in incidence from drug to drug. Providers caring for

patients being treated with protease inhibitors must be cautious for adverse events, notably those involving altered and gastrointestinal

problems, hence the use of statins and proton pump inhibitors.

Statins are HMG-CoA reductase inhibitors that are widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. The mechanism of action is via competitive inhibition of HMG-CoA reductase which catalyzes the reduction of HMG-CoA to mevalonate, the rate limiting step in hepatic cholesterol biosynthesis. Inhibition of this enzyme decreases the cholesterol synthesis leading to an upregulation in LDL receptors in the , and this increases LDL uptake by hepatocytes resulting in a decrease of LDL cholesterol in the bloodstream. Statins are considered safe, well tolerated and efficient treatment of high cholesterol. They are associated Group 47 :Orido/Samantha 5

with two important side effects, asymptomatic elevation in liver and severe myotoxicity. Myotoxicity can be myopathy defined by

muscle symptoms and creatine kinase levels above a 10-fold upper limit of normal. Myopathy occurrences under statin treatment ranges from

muscle pain with or without serum creatine phosphokinase (CPK) elevation to fatal with marked CPK elevation [7]. The risk of adverse events can increase with concentration therefore dosage and drug-drug interactions may increase the risk of adverse events. Statins are increasingly prescribed in the HIV-infected population because of its higher rate of lipid disorders resulting from HIV treatment. Protease inhibitors are currently used in combination with two nucleoside reverse transcriptase inhibitors in antiretroviral therapy (ART). All Protease inhibitors, except and in some cases atazanavir, are -boosted to improve the pharmacokinetic properties and enhance plasma exposure therefore a greater chance of drug interaction. [7]

Proton pump inhibitors are used to reduce gastric acid production. They inhibit the H-K-ATPase enzyme system selectively at the

secretory surface of the gastric parietal cells. Many HIV-infected patients experience clinically significant alterations in gastric pH levels, and concomitant use of acid-suppressing therapies, including over-the-counter medicines, is commonplace. A survey of 200 HIV-1–infected patients found that greater than 40% of patients on a PI-containing regimen had used proton pump inhibitors (PPIs), either since starting highly active antiretroviral therapy or within the previous 12 months [6]. Significant pharmacokinetic interactions can result between PPIs and some PIs, most

notably atazanavir and , whereas others such as , , and are largely free of such interactions [7]. Both

atazanavir and indinavir depend on an acidic gastric environment for adequate in vivo dissolution and absorption. All PPIs can raise gastric pH to

greater than 3.5 for 24 hours after dosing and maintain this acid-suppressing activity for 3 to 5 days. Therefore, concomitant use of PPIs could lead

to sub therapeutic PI concentrations, increasing the risk of virologic failure and development of drug resistance. For instance, in a lecture paper by Group 47 :Orido/Samantha 6

Zhu and group it states that 40 mg given 2 hours prior to atazanavir/ritonavir 300/100 mg to healthy volunteers decreased atazanavir

by approximately 75% relative to atazanavir/ritonavir alone [9].

The purpose of this study is to formally evaluate the effect of lansoprazole, dexlansoprazole, omeprazole, pantoprazole and rabeprazole on the pharmacokinetics of atazanavir and lovastatin and simvastatin on the pharmacokinetics and pharmacodynamics of PIs (atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinvir, and ).

Fig. 1: Chemical structures of HMG-CoA reductase inhibitors (statins). The ring is underlined in green and the efficacious acid moiety is underlined in red Group 47 :Orido/Samantha 7

METHODS

This study is a systematic review evaluation of primary literature articles evaluating the interactions between protease inhibitors

(atazanavir, darunavir, ritonavir, fosamprenavir, indinavir, lopinavir, nelfinavir, , tipranavir) with statins (simvastatin and Lovastatin)

and Atazanavir with proton pump inhibitors (dexlansoprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole).

Article inclusion criteria. Articles of interest for study must meet the following inclusion criteria: All literature articles, including

randomized controlled trials, cohort study, case series, case report, and cross-sectional study involving protease inhibitors (atazanavir, darunavir,

ritonavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir) with statins (simvastatin and Lovastatin)and atazanavir with proton

pump inhibitors (dexlansoprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole). All ages, genders, healthy patients, or with HIV or AIDS.

The following exclusion criteria were used: studies that solely focused protease inhibitors, statins or proton pump inhibitors; studies that do not

have protease inhibitor.

We included all trials looking at the interactions between protease inhibitors with statins and protease inhibitors with proton pump

inhibitors. The primary outcomes that we will be interested in contain evidence suggesting an interaction such as pharmacokinetic parameters (e.g,

AUC, Cmin, Cmax, Tmax); therapeutic benefit (e.g., viral load, CD4 count, absolute neutrophil count (ANC) and adverse events (e.g.

hyperglycemia, , abnormal liver function, change in heart rhythm, increased risk of myopathy).

A systematic literature search using Pubmed, EMBASE and google scholar (secondary source), with no date and language restriction. The

selection of primary sources will be based on a review of title, keywords (such as HIV, pharmacokinetics, AIDS, and/or human immunodeficiency

virus) and names of each drug in the interacting pair with Boolean connector “AND”. For protease inhibitors the drug names “atazanavir,”

“darunavir,” “ritonavir”, “fosamprenavir”, “indinavir”, “lopinavir”, “nelfinavir”, “saquinavir”, and “tipranavir” along with the general search term Group 47 :Orido/Samantha 8

“protease inhibitors” will be used. For proton pump inhibitors the drug names: “dexlansoprazole”, “lansoprazole”, “omeprazole”, “pantoprazole”, and “rabeprazole” along with the general search term “proton pump inhibitors” will be used. For statins the drug names “lovastatin” and

“simvastatin” along with the general search term “statin” will be used. The search will be limited to studies involving humans and in English language (articles translated to English will also be used). All selected studies will then be reviewed against our set of inclusion criteria designed to identify whether or not a study can help to answer our specified research questions. In particular, our aim will be to identify whether a study describes any drug interaction between the drugs we are looking at. Reference lists of review articles and relevant trials will also be searched. Two investigators will independently extract relevant information, compare and resolve any difference in procedure. Information on allocation methods will be sought from the original authors if it’s not available in the published reports.

Instrument and data collection: We will use a literature assessment tool called drug interaction Probability Scale (DIPS) which was developed by Horn et. al. to evaluate the quality of DDI case reports. If the total DIPs score is >8 then that will suggest a highly probable of drug interaction. Lower values of 5-8 probable of drug interaction, 2-4 possible of drug interaction, and <2 doubtful of drug interaction. A data collection sheet will be used to obtain article information such as citation information, patients studied, trial duration, age (minimum, maximum, and average age), gender study type (experimental vs non experimental), dose used, outcome and DIPS score.

Group 47 :Orido/Samantha 9

RESULTS

A total of two hundred and forty-six references from PubMed, EMBASE and Google Scholar being used as a secondary source were identified. We then applied filters of English only, humans and primary literature for the database searches along with all of references from facts and comparisons and Micromedex. At total 34 articles met our criteria. Of the 34 articles initially selected 20 were eliminated upon further review.

Ten of these articles were copies of the previously acknowledged case studies. Two studies focused on pharmacokinetic enhancement through

CYP3A inhibition, they only looked at how protease inhibitors can interact with other cyp3A4. One study looked at the IDSA guidelines on statin use and it’s anticipated adverse events. The other seven studies were either evidence-based review, evaluation of statins or PPIs use, and one was talking about indinavir use with rabeprazole. At the end we remained with 14 studies to evaluate for our final analysis. Of the 14 articles, eight (3 drug trials, 3 case reports, 1 was post-script letter and 1 was a retrospective cohort study) of them were between statins and PIs (table 1) while seven of them were between PPIs and Atazanavir (table 2).

Of the 14 reviewed articles 14 of them were case reports (21%) (including the post-script letter). All 14 trials/case reports were awarded

DIPS score that fell between probable and highly probable, 10(71%) had a probable score while 4(29%) had a score of highly probable.

Supplementary information gathered on simvastatin, lovastatin interaction includes severe diarrhea, muscle weakness leading to hospitalization and in one case report leading to death.

Group 47 :Orido/Samantha 10

Table 1 Studies of simvastatin and Protease inhibitors

Test regimen Reference Design Patient n Reference Protease Statin AUC Cmax Comments populatio regimen Inhibitor n Hsyu et al. Open-label, Healthy 32 Simvastatin Nelfinavir Simvastatin co- ↑ 505 % ↑517 % ADE: 2001 [1] sequential, 20 mg 1250 mg BID administered with Diarrhea multiple-dose, NFV after 14 days Rash single center on Simvastatin alone Migraine headache study ↓Fasting cholesterol ↓LDL Fichtenbau Randomized HIV 67 Simvastatin Atazanavir/ Simvastatin ↑59% ↑328% ADE: m et al 2002 phase 1, open Serone- 40 mg/day ritonavir 300 40mg/day Diarrhea label, multiple gative mg BID administered with GI upset dose Sequinavir RTV after 14 days or Concentration increased 400 mg/day simvastatin alone 30-fold BID Simvastatin 40 mg/day administered with SQV after 14 days of simvastatin alone.

Methaneeth Open-label, Healthy Simvastatin Nelfinavir Simvastatin co- Concentration Increased orn et al sequential, 20 mg/day administered with 6-fold. 2014 multiple dose, NFV after 14 days single center on Simvastatin alone Hare et al Case report HIV 1(70- Simvastatin Nelfinavir Simvastatin Muscle weakness 2002 year-old 80 mg /day 750 mg TID concurrent with Diarrhea white Nelfinavir Acute renal failure male Oliguria Metabolic acidosis Elevated troponin-1 Elevated creatine kinase Rhabdomyolysis Death Group 47 :Orido/Samantha 11

Ginelle et al Case report HIV 1(72- Simvastatin Atazanavir Simvastatin Weakness 2007 year-old 80 mg/day 400 mg at concurrent with white bedtime Atazanavir 27days Muscle pain male and amiodarone for Increased creatine kinase 400 mg daily 7 days Dark orange urine for 7 days Oliguric renal failure then 200 mg daily. Cheng et al Case report HIV 1(51- Simvastatin Indinavir 800 Simvastatin Elevated aspartate 2002 year-old 20 mg/day mg BID concurrent with transaminase, LDH, alanine white Ritonavir 100 Indinavir and transaminase. woman mg BID ritonavir. Ritonavir Rhabdomyolysis. added 1 week before admission

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; 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.

Group 47 :Orido/Samantha 12

Table 2 Studies of Proton pump inhibitors and Protease inhibitors

Test regimen Reference Design Patient n Reference Protease Statin AUC Cmax Comments population regimen Inhibitor Zhu et al Cohort Healthy 56 Atazanavir ATV 400 mg OMP 20 mg QAM ↓38 % 2011 400mg qd qd 12 h before ATV/r ↓42 % ATV/r OMP 20 mg QAM ↓37 % 300/100 mg 1 h before ATV/r qd OMP 20 mg 12 h ATV/r after ATV/r 400/100 mg qd Agarwala et Randomized, Healthy 48 Atazanavir/ ATV/r OMP 40 mg qd, 2 h ↓76% ↓72% al. 2005 parallel group, ritonavir 300/100 mg before open label, 300/100 mg qd qd ATV/r multiple doses. ATV/r OMP 40 mg qd, 2 h ↓70% ↓66% 300/100 mg before qd1cola ATV/r ATV/r OMP 40 mg qd, 2 h ↓61% ↓66% 400/100 mg before qd ATV/r Luber et al. Randomized, Healthy 19 ATV/r 300/100 ATV/r OMP 20 mg single . 2006 Cross Over, mg qd AM 300/100 mg dose Open Label, qd Am PM multiple doses, ATV/r OMP 20 mg qd PM ↓27% ↓33% 300/100 mg qd AM Tomilo et al. Cross Over, Healthy 9 ATV 400 mg ATV 400 mg LANS 60 mg qd x ↓94% ↓91% Standard Lansoprazole dose 2006 Open Label, single dose single 2 is 30mg dose doses Agarwala et R, PG, OL, Healthy 48 ATV 400 mg ATV 400 mg OMP40 mg qd, 2 h ↓94% ↓96% al. 2005 multiple doses qd qd before ATV 400 mg ATV qd 1 ↓93% ↓94% Group 47 :Orido/Samantha 13

Cola OMP 40 mg qd, 2h ATV/r before ↓50% ↓73% 300/100 qd ATV OMP 40 mg qd, 2 h before ATV/r

Klein et al. R, PG, OL, Healthy 10 ATV/r 300/100 ATV/r OMP 40 mg qd, 1.5 62 59 RTV AUC ↓ 16%, 2006 [//] multiple doses mg qd 300/100 mg h Cmax and Cmin no qd before ATV/r change Faber et al Ranndomized, Healthy 8 Atazanavir/ atazanavir/ Rebeprazole 200 ↓70% ↓35% 2016 [//] single-dose, 3 Ritonavir ritonavir mg BID + period, 300/100 mg 300/100 mg atazanavir/ritonavir crossover 300/100 mg study

The ‘multiple doses’ design indicates that all agents are given for multiple doses, except where otherwise specified. 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, 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, randomized; TV or r, ritonavir; SQV, saquinavir; BID, two times a day; TPV, tipranavir.

Group 47 :Orido/Samantha 14

DISCUSSION

Simvastatin and Lovastatin

HIV-positive patients for the most part take numerous prescriptions, and consequently, drug-drug interaction between these drugs is an imperative issue for antiretroviral treatments. A significant number of these medications can interact with one another to change the pharmacodynamics of the medications. To get the right ideal dosing regimens for HIV-positive patients, it is essential to understand the right drug interaction between medications. In this review we investigated the interaction between HMG-CoA reductase inhibitors Simvastatin and

Lovastatin with HIV Protease Inhibitors and Atazanavir with Proton Pump Inhibitors (PPIs) because of the potential for drug-drug interaction and the potential of the co-administration of these medications.

Simvastatin and Lovastatin are administered in an inactive lipophilic lactone ring prodrug with higher lipophilicity which leads to better passive membrane permeability [7]. They are extensively metabolized by cytochrome P4503A in humans which has the highest potency for drug- drug interaction with other potent CYP3A like Protease inhibitors and therefore their co-administration is contraindicated. The first death associated with rhabdomyolysis in a patient due Simvastatin and protease inhibitors interaction was reported by Hare in 2002. In a brief reported by Hare and colleagues [16] in 2002, a 70-year-old white man was admitted to San Francisco VA medical center and was taking an antiretroviral therapy regimen of (300 mg/day), (150 mg b.i.d.) and nelfinavir (750 mg t.i.d.) at the time of admission. The HIV regimen had not changed in 12 years. The patient was given simvastatin 80 mg/day and complications started to develop after 3 weeks. He eventually passed away while still in the hospital. The brief report and the trial suggests administration of a protease inhibitors concurrent with simvastatin and lovastatin increase the steady state concentration significantly of the two. This independent studies and case reports evaluated the pharmacokinetics and pharmacodynamics properties of PIs and simvastatin and lovastatin [10,11,12,14,15,16,17]. All of those studies a had a Group 47 :Orido/Samantha 15

significant increase in AUC and Cmax. In a study by Hsyu et al. 2001[10] the AUC and Cmax increases by more than 500% for both. Most of the the

AUC and Cmax also increased 59% and 328% respectively [11]. Most of the case reports reported adverse events such as severe diarrhea, GI upset, metabolic acidosis, muscle pain, rhabdomyolysis [12,15,17], and one reporting death [16].

Atazanavir

Numerous studies have been done to assess the impact of proton pump inhibitors on atazanavir. Dependably across these trials PPIs have had a huge impact on atazanavir exposure. When Atazanavir 400 mg was given with omeprazole it has a significant impact by reducing the Cmax

and AUC. When atazanavir was combined with ritonavir 100 mg the impact on the Cmax and AUC was a lot better compared to atazanavir alone

[22,25]. Most of the studies performed by atazanavir/ritonavir 300/100 mg showed a similar pattern of interaction but a lesser degree due ritonavir

being added on. [22,25,27]. Administration of omeprazole 40 mg with atazanavir 400 mg with without cola decreased atazanavir AUC, Cmax and

Cmin by >93% compared to atazanavir alone. Administration of omeprazole 40 mg with atazanavir/ritonavir 300/100 mg decreased atazanavir

AUC by 50% and Cmax 73% relative to atazanavir alone [25]. In the study by Luber et al. 2007 omeprazole 20 mg reduced atazanavir exposure

(area under the concentration curve and the minimum drug concentration (Cmin) by 27% each [27].

The interesting thing providers should keep an eye on appears that the lower the PPIs dose and a long time-based separation in the administration with atazanavir/ritonavir may have less of an effect on the atazanavir pharmacokinetics parameters, the highest dose of PPIs given 2 hours before atazanavir/ritonavir. [22].

Group 47 :Orido/Samantha 16

CONCLUSION

In conclusion, protease Inhibitors increased the AUC and Cmax of simvastatin by approximately 500% and 517 respectively. Therefore, simvastatin and Lovastatin are not recommended co-administration with a Protease Inhibitors. Other statins can be used like , rosuvastatin and pravastatin which is the main statin recommended. Atazanavir can be administered with PPIs but if possible, change of an acid reducing agent may be warranted. Providers should keep a close eye to those patients taking atazanavir and PPIs and consider a change to H2RA.

Group 47 :Orido/Samantha 17

REFERENCE:

1. UNAIDS. 2018 Global AIDS Update: Miles to go—closing gaps, breaking barriers, righting injustices; July 2018. UNAIDS. AIDSinfo

website; accessed January 2019, available at: http://aidsinfo.unaids.org/. UNAIDS. Core Epidemiology Slides; January 2019.

2. UNAIDS. 2018 Global AIDS Update: Miles to go—closing gaps, breaking barriers, righting injustices; July 2018. UNAIDS. AIDSinfo

website; accessed January 2019, http://aidsinfo.unaids.org/. UNAIDS. Core Epidemiology Slides; January 2019. UNAIDS. Fact Sheet –

Latest statistics on the status of the AIDS epidemic 2018; January 2018 UNAIDS. UNAIDS data 2018, January 2019.

3. Office of the Commissioner. “HIV/AIDS History of Approvals - HIV/AIDS Historical Time Line 2000 - 2010.” U S Food and Drug

Administration Home Page, Office of the Commissioner, www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm.

4. Prescribing information. Reyataz (atazanavir). Princeton, NJ: Bristol-Myers Squibb Company, November 2018.

5. Prescribing information. Zocor (simvastatin). Whitehouse Station, NJ: Merck & Co., Inc., November 2018

6. Prescribing information. Mevacor (lovastatin). Whitehouse Station, NJ: Merck & Co., Inc., November 2018.

7. Chauvin, B., Drouot, S., Barrail-Tran, A. et al. Clin Pharmacokinet (2013) 52: 815. https://doi-

org.ezproxy4.library.arizona.edu/10.1007/s40262-013-0075-4. Accessed May 2018.

8. Béïque, L, et al. “Interactions between Protease Inhibitors and Acid-Reducing Agents: a Systematic Review.” HIV Medicine, vol. 8, no. 6,

2007, pp. 335–345., doi:10.1111/j.1468-1293.2007.00482. x. Accessed November 1028

9. Chastain, Daniel B., et al. “Evidence-Based Review of Statin Use in Patients with HIV on Antiretroviral Therapy.” Journal of Clinical &

Translational Endocrinology, vol. 8, 2017, pp. 6–14., doi: 10.1016/j.jcte.2017.01.004. Accessed November 2018 Group 47 :Orido/Samantha 18

10. Hsyu, P.-H., et al. “Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Atorvastatin and Simvastatin.” Antimicrobial Agents and Chemotherapy, vol. 45, no. 12, 2001, pp. 3445–3450.,

doi:10.1128/aac.45.12.3445-3450.2001. Accessed November 2018

11. Al, Fichtenbaum Et. “Pharmacokinetic Interactions between Protease Inhibitors and Statins in HIV Seronegative Volunteers.” Aids, vol.

17, no. Supplement 4, 2003, pp. 109–110., doi:10.1097/00002030-200317004-00017. Accessed November 2018.

12. Schmidt, G. A., et al. “Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin, Amiodarone, and

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. Accessed November 2018

13. Dubé, Michael P., and Joseph J. Cadden. “Lipid Metabolism in Treated HIV Infection.” Best Practice & Research Clinical Endocrinology

& Metabolism, vol. 25, no. 3, 2011, pp. 429–442., doi: 10.1016/j.beem.2011.04.004.

14. Methaneethorn, Janthima, et al. “Pharmacokinetic Modeling of Simvastatin, Nelfinavir and Their Interaction in Humans.” 2014 36th

Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2014, doi:10.1109/embc.2014.6944925.

15. Coyne, K. M, et al. “Simvastatin Co-Prescribed with Protease Inhibitors despite Dangerous Drug Interactions.” Sexually Transmitted

Infections, vol. 83, no. 6, 2007, pp. 498–499., doi:10.1136/sti.2007.026070.

16. Hare, C. Bradley, et al. “Simvastatin‐Nelfinavir Interaction Implicated in Rhabdomyolysis and Death.” Clinical Infectious Diseases, vol.

35, no. 10, 2002, doi:10.1086/344179.

17. Cheng, Cindy H., et al. “Rhabdomyolysis Due to Probable Interaction between Simvastatin and Ritonavir.” American Journal of Health-

System Pharmacy, vol. 59, no. 8, 2002, pp. 728–730., doi:10.1093/ajhp/59.8.728. Group 47 :Orido/Samantha 19

18. Dubé, Michael P., et al. “Guidelines for the Evaluation and Management of in Human Immunodeficiency Virus (HIV)-

Infected Adults Receiving Antiretroviral Therapy: Recommendations of the HIV Medicine Association of the Infectious Disease Society

of America and the Adult AIDS Clinical Trials Group.” Clinical Infectious Diseases, vol. 37, no. 5, 2003, pp. 613–627.,

doi:10.1086/378131.

19. Eagling, V. A., et al. “Differential Inhibition of Cytochrome P450 Isoforms by the Protease Inhibitors, Ritonavir, Saquinavir and

Indinavir.” British Journal of Clinical Pharmacology, vol. 44, no. 2, 1997, pp. 190–194., doi:10.1046/j.1365-2125.1997.00644. x.

20. Josephson, F. “Drug-Drug Interactions in the Treatment of HIV Infection: Focus on Pharmacokinetic Enhancement through CYP3A

Inhibition.” Journal of Internal Medicine, vol. 268, no. 6, 2010, pp. 530–539., doi:10.1111/j.1365-2796.2010.1102301. x.

21. Kis, Olena, et al. “In Vitro and In Situ Evaluation of PH-Dependence of Atazanavir Intestinal Permeability and Interactions with Acid-

Reducing Agents.” Pharmaceutical Research, vol. 31, no. 9, 2014, pp. 2404–2419., doi:10.1007/s11095-014-1336-0.

22. Zhu, Li, et al. “Effect of Low-Dose Omeprazole (20 Mg Daily) on the Pharmacokinetics of Multiple-Dose Atazanavir With Ritonavir in

Healthy Subjects.” The Journal of Clinical Pharmacology, vol. 51, no. 3, 2011, pp. 368–377., doi:10.1177/0091270010367651.

23. Faber, Kathleen Panter, et al. “Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in

Atazanavir Absorption.” Pharmaceutical Research, vol. 34, no. 3, 2016, pp. 619–628., doi:10.1007/s11095-016-2090-2.

24. Sahloff, Eric G, and Joan M Duggan. “Clinical Outcomes Associated with Concomitant Use of Atazanavir and Proton Pump

Inhibitors.” Annals of Pharmacotherapy, vol. 40, no. 10, 2006, pp. 1731–1736., doi:10.1345/aph.1h217. Group 47 :Orido/Samantha 20

25. Agarwala S, Gray K, Eley T, Wang Y, Hughes E, Grasela D. Pharmacokinetic interaction between atazanavir and omeprazole in healthy

subjects. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, 24–27 July 2005

[Abstract WePe3.3C08].

26. Klein C, Chiu YL, Cai Y et al. Lack of effect of acid reducing agents on the pharmacokinetics of lopinavir/ritonavir tablet formulation.

13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, 5–8 February 2006 [Abstract 578].

27. Luber, Ad, et al. “Steady-State Pharmacokinetics of Once-Daily Fosamprenavir/Ritonavir and Atazanavir/Ritonavir Alone and in

Combination 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.

28. Drug Interaction Probability Scale (DIPS) | PmidCALC Online Calculators, www.pmidcalc.org/?sid=17389673&newtest=Y.

Table 3: Documentation and severity listing in Lexicomp

Object drug Precipitant Drug Severity Documentation Simvastatin Atazanavir Contraindicated Good Darunavir/Ritonavir Contraindicated Good Fosamprenavir Contraindicated Fair Indinavir Contraindicated Good Lopinavir/ritonavir Contraindicated Good Nelfinavir Contraindicated Good Ritonavir Contraindicated Good Saquinavir Contraindicated Good Tipranavir Contraindicated Fair

Lovastatin Atazanavir Contraindicated Fair Group 47 :Orido/Samantha 21

Darunavir/Ritonavir Contraindicated Fair Fosamprenavir Contraindicated Fair Indinavir Contraindicated Fair Lopinavir/ritonavir Contraindicated Fair Nelfinavir Contraindicated Fair Ritonavir Contraindicated Fair Saquinavir Contraindicated Fair Tipranavir Contraindicated Fair

Table 4: Documentation and severity listing in Lexicomp

Object Precipitant Drug Risk Rating Severity Documentation Atazanavir Dexlansoprazole D: Consider therapy Major Good modification Lansoprazole D: Consider therapy Major Good modification Omeprazole D: Consider therapy Major Good modification Pantoprazole D: Consider therapy Major Good modification Rebeprazole D: Consider therapy Major Good modification