Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment.

INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.

Prevalence of Potential Drug-Drug Interactions in Patients of the Swiss HIV Cohort Study in the Era of HIV Integrase Inhibitors.

BACKGROUND: Prevalence of potential drug-drug interactions (PDDIs) between antiretroviral drugs (ARVs) and co-medications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of human immunodeficiency virus (HIV) integrase inhibitors (INIs), characterized by more favorable interaction profiles. METHODS: The prevalence of PDDIs in treated HIV-positive individuals was assessed for the period 01-12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged), or of weak clinical significance (yellow flagged). RESULTS: In 9298 included individuals, median age was 51 years (IQR, 43-58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and nonnucleoside reverse transcriptase inhibitor (NNRTIs) (32%)-based regimens. In the entire cohort, 68% received ≥1 co-medication, 14% had polypharmacy (≥5 co-medications) and 29% had ≥1 PDDI. Among individuals with co-medication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber-mostly with cardiovascular drugs-and 20% yellow-flagged PDDIs) compared to 59% in 2008. Two percent had red-flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared with 2008, fewer individuals received boosted ARVs (-24%) and NNRTIs (-13%) but the use of co-medications was higher. CONCLUSIONS: Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for co-medications in this aging population impeded lower rates of PDDIs.

Polypharmacy and Drug-Drug Interactions in People Living With Human Immunodeficiency Virus in the Region of Madrid, Spain: A Population-Based Study.

BACKGROUND: Drug-drug interactions (DDIs) that involve antiretrovirals (ARVs) tend to cause harm if unrecognized, especially in the context of comorbidity and polypharmacy. METHODS: A linkage was established between the drug dispensing registry of Madrid and the Liverpool human immunodeficiency virus (HIV) DDI database (January 2017-June 2017). Polypharmacy was defined as the use of ≥5 non-HIV medications, and DDIs were classified by a traffic-light ranking for severity. RESULTS: A total of 22 945 people living with HIV (PLWH) and 6 613 506 individuals without HIV had received medications. ARV regimens were predominantly based on integrase inhibitors (51.96%). Polypharmacy was higher in PLWH (32.94%) than individuals without HIV (22.16%; P < .001); this difference was consistently observed across all age strata except for individuals ≥75 years. Polypharmacy was more common in women than men in both PLWH and individuals without HIV. The prevalence of contraindicated combinations involving ARVs was 3.18%. Comedications containing corticosteroids, quetiapine, or antithrombotic agents were associated with the highest risk for red-flag DDI, and the use of raltegravir- or dolutegravir-based antiretroviral therapy was associated with an adjusted odds ratio of 0.72 (95% confidence interval, .60-.88; P = .001) for red-flag DDI. CONCLUSIONS: Polypharmacy was more frequent among PLWH across all age groups except those aged ≥75 years and was more common in women. The detection of contraindicated medications in PLWH suggests a likely disconnect between hospital and community prescriptions. Switching to alternative unboosted integrase regimens should be considered for patients with risk of harm from DDIs.

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection.

BACKGROUND: In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria. METHODS AND FINDINGS: This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs. CONCLUSIONS: There is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of recommendation criteria to DDI data is feasible, and allows the assessment of DDIs to be robust, consistent, transparent and evidence-based.

Prevalence of potential drug-drug interactions involving antiretroviral drugs in a large Kenyan cohort.

BACKGROUND: Clinically significant drug-drug interactions (CSDIs) involving antiretrovirals are frequent and under-recognized in developed countries, but data are lacking for developing countries. METHODOLOGY AND PRINCIPAL FINDINGS: To investigate the prevalence of CSDIs between antiretrovirals and coadministered drugs, we surveyed prescriptions dispensed in a large HIV clinic in Kenya. Of 1040 consecutive patients screened, 996 were eligible for inclusion. CSDIs were defined as 'major' (capable of causing severe or permanent damage, contraindicated, avoid or not recommended by the manufacturer, or requiring dose modification) or 'moderate' (manufacturers advise caution, or close monitoring, or capable of causing clinical deterioration). A total of 334 patients (33.5%) were at risk for a CSDI, potentially lowering antiretroviral drug concentrations in 120 (12%) patients. Major interactions most frequently involved rifampicin (12.4%, mostly with efavirenz) and azoles (2.7%) whereas moderate interactions were frequently azoles (13%), steroids (11%), and antimalarials (3%). Multivariable analyses suggested that patients at risk for CSDIs had lower CD4 counts (P = 0.006) and baseline weight (P = 0.023) and WHO Stage 3 or 4 disease (P≤0.007). Risk for CSDIs was not associated with particular regimens, although only 116 (11.6%) patients were receiving WHO second line regimens. CONCLUSIONS: One in three patients receiving antiretrovirals in our programme were at risk of CSDIs. Strategies need to be urgently developed to avoid important drug interactions, to identify early markers of toxicity and to manage unavoidable interactions safely in order to reduce risk of harm, and to maximize the effectiveness of mass antiretroviral deployment in Africa.

Prevalence of comedications and effect of potential drug-drug interactions in the Swiss HIV Cohort Study.

BACKGROUND: Potential drug-drug interactions (PDDIs) might expand with new combination antiretroviral therapies (ART) and polypharmacy related to increasing age and comorbidities. We investigated the prevalence of comedications and PDDIs within a large HIV cohort, and their effect on ART efficacy and tolerability. METHODS: All medications were prospectively recorded in 1,497 ART-treated patients and screened for PDDIs using a customized version of the Liverpool drug interactions database. RESULTS: Overall, 68% (1,013/1,497) of patients had a comedication and 40% (599/1,497) had > or = 1 PDDI. Among patients with comedication, 2% (21/1,013) had red-flag interactions (contraindicated) and 59% (597/1,013) had orange-flag interactions (potential dose adjustment and/or close monitoring required). The latter involved mainly central nervous system drugs (49%), cardiovascular drugs (34%) and methadone (19%). In the multivariate analysis, factors associated with having a comedication were advanced age, female gender, obesity and HCV infection. Independent risk factors for PDDIs were regimens combining protease inhibitors and non-nucleoside reverse transcriptase inhibitors (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.44-6.48), > or = 2 comedications (OR 1.89, 95% CI 1.32-2.70), current illicit drug use (OR 2.00, 95% CI 1.29-3.10) and patients with HCV infection (OR 1.74, 95% CI 1.19-2.56). Viral response was similar in patients with and without PDDIs (84.5% versus 86.4%; P=0.386). During follow-up, ART was modified in 134 patients with comedication regardless of the presence of PDDIs (P=0.524). CONCLUSIONS: PDDIs increase with complex ART and comorbidities. No adverse effect was noted on ART efficacy or tolerability; however, most PDDIs affected comedication but were manageable through dose adjustment or monitoring.

HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms.

OBJECTIVE: OATP1B1 and OATP1B3 are major hepatic drug transporters whilst OATP1A2 is mainly located in the brain but is also located in liver and several other organs. These transporters affect the distribution and clearance of many endobiotics and xenobiotics and have been reported to have functional single nucleotide polymorphisms (SNPs). We have assessed the substrate specificities of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir. METHODS: SLCO1A2, SLCO1B1 and SLCO1B3 were cloned, verified and used to generate cRNA for use in the Xenopuslaevis oocyte transport system. Using the oocyte system, antiretrovirals were tested for their substrate specificities. Plasma samples (n=349) from the Liverpool therapeutic drug monitoring registry were genotyped for SNPs in SLCO1A2, SLCO1B1 and SLCO1B3 and associations between SNPs and lopinavir plasma concentrations were analysed. RESULT: Antiretroviral protease inhibitors, but not non-nucleoside reverse transcriptase inhibitors, are substrates for OATP1A2, OATP1B1 and OATP1B3. Furthermore, ritonavir was not an inhibitor of OATP1B1. The 521T>C polymorphism in SLCO1B1 was significantly associated with higher lopinavir plasma concentrations. No associations were observed with functional variants of SLCO1A2 and SLCO1B3. CONCLUSION: These data add to our understanding of the factors that contribute to variability in plasma concentrations of protease inhibitors. Further studies are now required to confirm the association of SLCO1B1 521T>C with lopinavir plasma concentrations and to assess the influence of other polymorphisms in the SLCO family.