Multidrug-resistant HIV-1 Infection Research Articles

Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals.

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape.

Pharmacokinetics of long-acting lenacapavir in participants with hepatic or renal impairment.

Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.

HIV-1 capsid and viral DNA integration.

HIV-1 capsid protein (CA)-independently or by recruiting host factors-mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell. Research in the recent years have established that CA is multifunctional and genetically fragile of all the HIV-1 proteins. Accordingly, CA has emerged as a validated and high priority therapeutic target, and the first CA-targeting antiviral drug was recently approved for treating multi-drug resistant HIV-1 infection. However, development of next generation CA inhibitors depends on a better understanding of CA's known roles, as well as probing of CA's novel roles, in HIV-1 replication. In this timely review, we present an updated overview of the current state of our understanding of CA's multifunctional role in HIV-1 replication-with a special emphasis on CA's newfound post-nuclear roles, highlight the pressing knowledge gaps, and discuss directions for future research.

Rescue therapy with an albuvirtide-based antiretroviral regimen in an HIV-infected child with multidrug resistance and multiple opportunistic infections: a case report

BackgroundManaging multidrug-resistant (MDR) HIV infections in children is particularly challenging due to the lack of experience with new drugs in the pediatric setting. Second-line albuvirtide (ABT) with an optimized antiretroviral background therapy was approved for adults and adolescents after first-line treatment failure. This paper describes the treatment outcomes and adverse effects of an ABT-based dual-active antiretroviral treatment regimen in a child with MDR HIV strains.Case presentationA 13 year-old Chinese female patient infected with MDR HIV strains showed a decrease in viral load (from 4.48 log10 to 1.73 log10) and an increase in CD4 + T cells (from 15 to 308 cells/µl) after 12 months of treatment with an ABT-based antiretroviral regimen. The child showed no relevant drug-related adverse reactions.ConclusionsThe case reported here could suggest that an ABT-based antiretroviral therapy might be beneficial and without relevant toxicity in children with MDR HIV. Infectiologists specializing in managing HIV should be prepared to manage an increasing number of children with MDR HIV. ABT might be a new treatment option for MDR HIV infection in children.

Green-adapted spectrophotometric determination of fostemsavir based on selective bromophenol blue extraction; reduction of hazardous consumption using computational calculations

A computationally-assisted and green spectrophotometric method has been developed for the determination of fostemsavir, a recently FDA-approved drug used in combination with antiretroviral drugs to treat multidrug-resistant HIV-1 infection. The method was developed using computational studies and solvent selection based on green chemistry principles. The density functional theory method was employed to identify bromophenol blue as the preferred acid dye for efficient extraction of fostemsavir. The solvent selection process involved a careful evaluation of the green ranking of solvents, which led to the use of water as the solvent. The method involved the extraction of fostemsavir with bromophenol blue to form a yellow ion-pair complex, which exhibited maximally sharp peaks at 418 nm, enabling sensitive visible spectrophotometric determination of fostemsavir in bulk and pharmaceutical preparations. The extraction procedures were optimized, and the method was demonstrated to be sensitive over the concentration range of 2–12 μg/mL fostemsavir. Furthermore, the method was evaluated with respect to green chemistry principles using the analytical eco-scale, the green analytical method index, and analytical greenness metric approach, all of which confirmed that the data obtained by the proposed method were environmentally acceptable.

Lenacapavir (Sunlenca®) for the treatment of HIV-1

STRUCTURE: Lenacapavir (previously GS-6207, brand name Sunlenca®) is a small molecule that selectively targets the HIV-1 capsid protein (CA, p24), which is a structural component of the virus. This is the first FDA-approved drug in the class of capsid protein inhibitors for clinical use in heavily treatment-experienced patients with multidrug-resistant HIV-1 infection. It has a molecular formula of C39H31ClF10N7O5S2 and a molecular weight of 968.28 g/mol.

Lenacapavir: a twice-yearly treatment for adults with multidrug-resistant HIV infection and limited treatment options

Introduction Lenacapavir , the compoundreviewed in this paper, is a novel, potent, and long-acting first-in-classHIV-1 capsid inhibitor that was granted breakthrough therapy designation forHIV treatment by the U.S. Food and Drug Administration in May 2019. Lenacapavirwas subsequently approved, in combination with other antiretroviral agents, forthe treatment of multidrug-resistant HIV in people with HIV who have limitedtreatment options due to safety, intolerance and resistance considerations,based on clinical trial data which demonstrated its efficacy, tolerability, andsafety for that population. Areas Covered This review draws uponpublished and unpublished data of lenacapavir (GS-6207) to discuss itschemistry, mechanism of action, pharmacokinetic and pharmacodynamic properties,as well as efficacy and safety observed in clinical trials; and an expertopinion section discusses its clinical uses, advantages, limitations, andpotential future applications. Expert Opinion Lenacapavir should beused in combination with at least 1 or 2 additional fully active agents, wherepossible, and adherence support is critical for selected companion drugs(particularly if self-administered) to optimize efficacy and preventtreatment-emergent resistance to lenacapavir. Providers should pay attention todrug-drug interactions when initiating lenacapavir.

Lenacapavir (Sunlenca) for multidrug-resistant HIV.

The FDA has approved oral and injectable formulations of the HIV-1 capsid inhibitor lenacapavir (Sunlenca – Gilead) for use with other antiretroviral drugs to treat multidrug-resistant HIV-1 infection (MDR-HIV) in heavily treatment-experienced adults whose current regimen is failing. Lenacapavir is the third drug to be approved exclusively for treatment of MDR-HIV; the intravenously administered CD4-directed antibody ibalizumab-uiyk (Trogarzo) and the orally administered HIV-1 gp120-directed attachment inhibitor fostemsavir (Rukobia) were approved earlier.

Inflammation burden score in multidrug-resistant HIV-1 infection

Four-class drug-resistant (4DR) people living with HIV (PLWH) are a fragile population with a high burden of disease. No data on their inflammation and T-cell exhaustion markers are currently available. Inflammation, immune activation and microbial translocation biomarkers were measured through ELISA in 30 4DR-PLWH with HIV-1 RNA ≥50 copies/mL, 30 non-viremic 4DR-PLWH and 20 non-viremic non-4DR-PLWH. Groups were matched by age, gender and smoking habit. T-cell activation and exhaustion markers were assessed by flow cytometry in 4DR-PLWH. An inflammation burden score (IBS) was calculated from soluble marker levels and associated factors were estimated through multivariate regression. The highest plasma biomarker concentrations were observed in viremic 4DR-PLWH, the lowest ones in non-4DR-PLWH. Endotoxin core immunoglobulin G showed an opposite trend. Among 4DR-PLWH, CD38/HLA-DR and PD-1 were more expressed on CD4+ (p=0.019 and 0.034, respectively) and CD8+ (p=0.002 and 0.032, respectively) cells of viremic compared to non-viremic subjects. An increased IBS was significantly associated with 4DR condition, higher values of viral load and a previous cancer diagnosis. Multidrug-resistant HIV infection is associated with a higher IBS, even when viremia is undetectable. Therapeutic approaches aimed to reduce inflammation and T-cell exhaustion in 4DR-PLWH need to be investigated.

Strategies to overcome HIV drug resistance-current and future perspectives.

The availability of combined antiretroviral therapy (cART) has revolutionized the course of HIV infection, suppressing HIV viremia, restoring the immune system, and improving the quality of life of HIV infected patients. However, the emergence of drug resistant and multidrug resistant strains remains an important contributor to cART failure, associated with a higher risk of HIV-disease progression and mortality. According to the latest WHO HIV Drug Resistance Report, the prevalence of acquired and transmitted HIV drug resistance in ART naive individuals has exponentially increased in the recent years, being an important obstacle in ending HIV-1 epidemic as a public health threat by 2030. The prevalence of three and four-class resistance is estimated to range from 5 to 10% in Europe and less than 3% in North America. The new drug development strategies are focused on improved safety and resistance profile within the existing antiretroviral classes, discovery of drugs with novel mechanisms of action (e.g., attachment/post-attachment inhibitors, capsid inhibitors, maturation inhibitors, nucleoside reverse transcriptase translocation inhibitors), combination therapies with improved adherence, and treatment simplification with infrequent dosing. This review highlight the current progress in the management of salvage therapy for patients with multidrug-resistant HIV-1 infection, discussing the recently approved and under development antiretroviral agents, as well as the new drug targets that are providing a new avenue for the development of therapeutic interventions in HIV infection.

Lenacapavir for the Treatment of Heavily Treatment-experienced People with Multi-class Resistant HIV

Multidrug resistance to antiretroviral therapy, while uncommon, is associated with high rates of clinical progression and virologic failure. Lenacapavir is the first capsid inhibitor to be approved for the treatment of HIV infection in heavily treatment-experienced people with multi-resistant virus, who cannot be successfully treated with other available therapies due to resistance, intolerance or safety considerations. The key feature of lenacapavir is its long half-life, which allows its subcutaneous formulation to be administered every 6 months. This is crucial for a population with low adherence rates to antiretroviral therapy. This review discusses the characteristics of lenacapavir, including its mechanism of action, pharmacokinetics/pharmacodynamics and resistance profile, the key efficacy and safety data from clinical trials, and its place in the management of patients with multidrug-resistant HIV infection.

The Mosaico HIV Vaccine Study: A Step Back or a Stepping Stone for Future Vaccine Development?

Multidrug resistance to antiretroviral therapy, while uncommon, is associated with high rates of clinical progression and virologic failure. Lenacapavir is the first capsid inhibitor to be approved for the treatment of HIV infection in heavily treatment-experienced people with multi-resistant virus, who cannot be successfully treated with other available therapies due to resistance, intolerance or safety considerations. The key feature of lenacapavir is its long half-life, which allows its subcutaneous formulation to be administered every 6 months. This is crucial for a population with low adherence rates to antiretroviral therapy. This review discusses the characteristics of lenacapavir, including its mechanism of action, pharmacokinetics/pharmacodynamics and resistance profile, the key efficacy and safety data from clinical trials, and its place in the management of patients with multidrug-resistant HIV infection.

1585. Efficacy and safety of long-acting subcutaneous lenacapavir in heavily treatment-experienced people with multi-drug resistant HIV: Week 52 results

Abstract Background Lenacapavir (LEN), a potent first-in-class inhibitor of HIV-1 capsid function, is in development as a long-acting agent for treatment and prevention of HIV-1. Methods CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced (HTE) people with HIV-1 (PWH) with multidrug-resistance. 36 participants were randomized (2:1) to add oral LEN or placebo to their failing regimen. At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg (Q6M); those on placebo started the oral LEN lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, optimized background regimen (OBR) at D15. An additional 36 participants started OBR concurrent with LEN (oral lead-in → SC) in a non-randomized cohort. We report the Week (W) 52 efficacy and safety results from both cohorts. Results Of 72 participants enrolled, 25% were female, 38% Black, median age 52 years, 64% had CD4 < 200 cells/µL, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI), and 53% had OBR with 1 or no fully active agents. At W52, 78% (56/72) achieved VL< 50 c/mL and 82% (59/72) achieved VL< 200 c/mL via FDA Snapshot algorithm. CD4 count increased by a median 84 cells/µL (Q1 to Q3: 21 to 153) and the proportion of participants with CD4 count ≥200 cells/ul increased from 36% at baseline to 68% at W52. Ten participants had emergent LEN resistance (8 previously reported); 4 of 10 subsequently suppressed. The median (range) duration of follow up on LEN was 71 (13–111) weeks. One participant discontinued due to injection site nodule (Grade 1). The most common injection site reaction (ISR) was swelling (28% [20/72] and 17% [12/70] after the 1st and 2nd SC doses, respectively). Most ISRs were mild or moderate. The most common AEs (excluding injection site reactions) were nausea and diarrhea (14% each). Conclusion In HTE PWH, subcutaneous LEN was well tolerated and in combination with OBR led to high and sustained rate of virologic suppression at W52. These results support the potential role for LEN for treatment of multi-drug resistant HIV-1 infection. Disclosures Sorana Segal-Maurer, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|JANSSEN THERAPEUTICS: Honoraria|ViiV: Honoraria Benoit Trottier, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Jason Brunetta, M.D., Gilead Canada: Advisor/Consultant|Gilead Canada: Honoraria|Gilead Canada: Conference Attendance Sponsorship|Viiv Canada: Advisor/Consultant Hui Wang, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Nicolas A. Margot, MA, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Hadas Dvory-Sobol, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Martin S Rhee, MD, Gilead Sciences: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Jean-Michel Molina, MD; PhD, GIlead: Board Member|GIlead: Grant/Research Support|Merck: Board Member|Merck: Expert Testimony|ViiV: Board Member.

Development and validation of a liquid chromatography coupled to tandem mass spectrometry method for the monitoring of temsavir plasma concentrations in people living with HIV

A majority of people living with HIV (PLWH) now have access to HIV treatment with high antiviral potency and favorable tolerability profile. However, in some treatment experienced PLWH viral strains resistant to major current classes of antiretrovirals have emerged, usually due to periods with continued virus replication in the presence of failing drug regimens and thus selection pressure. In such context, new treatment options are therefore needed.Fostemsavir (RUKOBIA®) is the prodrug of temsavir, a first-in-class oral attachment inhibitor approved for the treatment of heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. In this case RUKOBIA® is part of a complex regimen of antiretroviral drugs, often in addition to other drugs for chronic co-morbidities (e.g., heart disease, diabetes mellitus, hepatic and renal impairment, etc). In such a multi-drug regimen context, therapeutic drug monitoring (TDM) of temsavir can be necessary to exclude or adjust for relevant drug-drug interactions. A highly selective assay by liquid chromatography method coupled to tandem mass spectrometry (LC-MS/MS) was therefore developed for the quantification of temsavir in human plasma. A convenient sample preparation using protein precipitation with acetonitrile followed by supernatant dilution was carried out. Temsavir and fostemsavir were separated in less than 2 min using a multi-step UPLC gradient, thus ensuring adequate quantification of temsavir. The assay for the quantification of temsavir was extensively validated over the large range of clinically relevant concentrations from 1 to 10,000 ng/mL, in accordance with international bioanalytical method guidelines. The method achieves excellent performance in terms of trueness (99.7 – 105.3%), repeatability and intermediate precision (both from 1.6% to 5.8%).This LC-MS/MS method is now part of the routine analyses of the Laboratory of the Service of Clinical Pharmacology of Lausanne (CHUV), Switzerland, as an integrated part of our general TDM Service for antiretrovirals.

Lenacapavir: First Approval.

Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human immunodeficiency virus type1 (HIV-1) being developed by Gilead Sciences Inc. It is available as an oral tablet and injectable solution, with the latter being a slow-release formulation to allow bi-annual subcutaneous administration. In August 2022, lenacapavir received its first approval in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen. This article summarizes the milestones in the development of lenacapavir leading to this first approval for the treatment of HIV-1 infection.

Evaluation of the pharmacokinetic drug-drug interaction between the antiretroviral agents fostemsavir and maraviroc: a single-sequence crossover study in healthy participants

Background Fostemsavir is an oral prodrug of temsavir, a first‐in‐class attachment inhibitor that binds HIV‐1 gp120, preventing initial HIV attachment and entry into host immune cells. Objective The pharmacokinetic interaction was determined between temsavir and maraviroc, a CCR5 allosteric inhibitor indicated for CCR5-tropic HIV-1 that may be co-administered with fostemsavir as part of combination antiretroviral therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Methods This was a Phase 1, open-label, single-sequence, 3-period crossover study evaluating the effect of fostemsavir on maraviroc pharmacokinetics and the effect of maraviroc on temsavir pharmacokinetics (ClinicalTrials.gov, NCT02480894). Fourteen healthy participants received fostemsavir 600 mg twice daily (BID) for 4 days in Period 1 (followed by a 3-day washout), maraviroc 300 mg BID for 5 days in Period 2, and fostemsavir 600 mg BID with maraviroc 300 mg BID for 7 days in Period 3. Study drugs were administered orally with a standard meal. Results Following fostemsavir and maraviroc co-administration, maraviroc area under the plasma concentration-time curve over the dosing interval (AUCτ) increased 25% (from 1914 to 2382 ng.h/mL) and maraviroc plasma concentration at the end of the dosing interval (Ctrough) increased 37% (from 36.5 to 49.9 ng/mL), but there was no change in maximum observed concentration (Cmax). Following fostemsavir and maraviroc co-administration, temsavir AUCτ and Cmax increased 10-13% and Ctrough decreased 10%. Conclusions Co-administration of fostemsavir and maraviroc did not result in clinically relevant changes in maraviroc or temsavir exposure. Fostemsavir and maraviroc may be co-administered without dose adjustment of either antiretroviral agent.

Fostemsavir: The first oral attachment inhibitor for treatment of HIV-1 infection.

The pharmacology, pharmacokinetics, and role in therapy of fostemsavir in management of HIV-1 infection are reviewed, with an emphasis on clinical efficacy and safety data from phase 2 and phase 3 clinical trials. Fostemsavir (Rukobia, ViiV Healthcare), is a prodrug of temsavir, a novel pyridine compound with potent activity against HIV-1. Fostemsavir, the first oral attachment inhibitor, was approved and granted the breakthrough therapy designation by the Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in heavily treatment-experienced adults. As absorption of temsavir is not altered with increased gastric pH, patients may take acid suppressive agents such as famotidine during fostemsavir therapy.Temsavir is primarily metabolized through hydrolysis but also via cytochrome P-450 (CYP) oxidation; therefore, coadministration of fostemsavir with strong CYP3A inducers such as rifampin, carbamazepine, phenytoin, mitotane, enzalutamide, or St John's wort is contraindicated because it may result in significantly lower temsavir exposure, which can ultimately impair virologic response. The most common adverse reactions associated with fostemsavir use include nausea, diarrhea, headache, abdominal pain, dyspepsia, fatigue, rash, and sleep disturbance. Fostemsavir may be an effective option for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Fostemsavir is a particularly attractive treatment option for patients who are no longer able to achieve viral suppression with use of currently available antiretroviral therapies and who are able to adhere to a twice-daily oral regimen.

The Cost-Effectiveness and Budget Impact of Ibalizumab-uiyk for Adults with Multidrug-Resistant HIV-1 Infection in the United States.

Ibalizumab-uiyk (ibalizumab) is a first-in-class, long-acting, postattachment HIV-1 inhibitor for adults with multidrug-resistant (MDR) HIV-1 infection. This analysis examines the cost-effectiveness and budget impact of ibalizumab treatment for this difficult-to-treat population in the United States. A Markov model followed cohorts of adults with MDR HIV-1 infection through two final lines of antiretroviral therapy: ibalizumab + optimized background therapy (OBT) or OBT alone followed by nonsuppressive therapy. Model inputs were based on ibalizumab clinical trial data, market uptake projections, and published literature, with costs in 2019 dollars. The cost-effectiveness analysis assessed costs and health outcomes from a health care sector perspective for individuals receiving ibalizumab + OBT versus OBT alone over a lifetime time horizon. The budget-impact analysis estimated the impact on payer budgets of the introduction of ibalizumab over 3 years for a hypothetical commercial health plan. Compared with individuals receiving OBT alone, individuals receiving ibalizumab + OBT incurred higher costs but lived longer, healthier lives, with an incremental cost of $133,040 per QALY gained. For a hypothetical commercial health plan with 1 million members, the introduction of ibalizumab + OBT was estimated to increase budgets by $217,260, $385,245, and $560,310 ($0.018, $0.032, and $0.047 per member per month) in years 1, 2, and 3, respectively. These results were found to be robust in sensitivity and scenario analyses. Ibalizumab may represent a cost-effective and affordable option to improve health outcomes for individuals with MDR HIV-1 infection.

Ibalizumab cost effective for multidrug-resistant HIV-1 infection in USA?

Ibalizumab cost effective for multidrug-resistant HIV-1 infection in USA?

1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models

BackgroundFostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines.MethodsMetformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMRResultsTMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposureConclusionBased on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTRDisclosuresXiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)