DeepARV: ensemble deep learning to predict drug-drug interaction of clinical relevance with antiretroviral therapy.

Drug-drug interaction (DDI) may result in clinical toxicity or treatment failure of antiretroviral therapy (ARV) or comedications. Despite the high number of possible drug combinations, only a limited number of clinical DDI studies are conducted. Computational prediction of DDIs could provide key evidence for the rational management of complex therapies. Our study aimed to assess the potential of deep learning approaches to predict DDIs of clinical relevance between ARVs and comedications. DDI severity grading between 30,142 drug pairs was extracted from the Liverpool HIV Drug Interaction database. Two feature construction techniques were employed: 1) drug similarity profiles by comparing Morgan fingerprints, and 2) embeddings from SMILES of each drug via ChemBERTa, a transformer-based model. We developed DeepARV-Sim and DeepARV-ChemBERTa to predict four categories of DDI: i) Red: drugs should not be co-administered, ii) Amber: interaction of potential clinical relevance manageable by monitoring/dose adjustment, iii) Yellow: interaction of weak relevance and iv) Green: no expected interaction. The imbalance in the distribution of DDI severity grades was addressed by undersampling and applying ensemble learning. DeepARV-Sim and DeepARV-ChemBERTa predicted clinically relevant DDI between ARVs and comedications with a weighted mean balanced accuracy of 0.729 ± 0.012 and 0.776 ± 0.011, respectively. DeepARV-Sim and DeepARV-ChemBERTa have the potential to leverage molecular structures associated with DDI risks and reduce DDI class imbalance, effectively increasing the predictive ability on clinically relevant DDIs. This approach could be developed for identifying high-risk pairing of drugs, enhancing the screening process, and targeting DDIs to study in clinical drug development.

A novel LC-MS/MS method for the determination of favipiravir ribofuranosyl-5'-triphosphate (T-705-RTP) in human peripheral mononuclear cells.

Favipiravir is a broad-spectrum antiviral that is metabolised intracellularly into the active form, favipiravir ribofuranosyl-5'-triphosphate (F-RTP). Measurement of the intracellular concentration of F-RTP in mononuclear cells is a crucial step to characterising the pharmacokinetics of F-RTP and to enable more appropriate dose selection for the treatment of COVID-19 and emerging infectious diseases. The described method was validated over the range 24 - 2280 pmol/sample. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and lysed using methanol-water (70:30, v/v) before cellular components were precipitated with acetonitrile and the supernatant further cleaned by weak anion exchange solid phase extraction. The method was found to be both precise and accurate and was successfully utilised to analyse F-RTP concentrations in patient samples collected as part of the AGILE CST-6 clinical trial.

Evaluating Radiation Exposure in Patients with Stable Chest Pain in the SCOT-HEART Trial.

Background In the Scottish Computed Tomography of the Heart (SCOT-HEART) trial in individuals with stable chest pain, a treatment strategy based on coronary CT angiography (CTA) led to improved outcomes. Purpose To assess 5-year cumulative radiation doses of participants undergoing investigation for suspected angina due to coronary artery disease with or without coronary CTA. Materials and Methods This secondary analysis of the SCOT-HEART trial included data from six of 12 recruiting sites and two of three imaging sites. Participants were recruited between November 18, 2010, and September 24, 2014, with follow-up through January 31, 2018. Study participants had been randomized (at a one-to-one ratio) to standard care with CT (n = 1466) or standard care alone (n = 1428). Imaging was performed on a 64-detector (n = 223) or 320-detector row scanner (n = 1466). Radiation dose from CT (dose-length product), SPECT (injected activity), and invasive coronary angiography (ICA; kerma-area product) was assessed for 5 years after enrollment. Effective dose was calculated using conversion factors appropriate for the imaging modality and body region imaged (using 0.026 mSv/mGy · cm for cardiac CT). Results Cumulative radiation dose was assessed in 2894 participants. Median effective dose was 3.0 mSv (IQR, 2.6-3.3 mSv) for coronary calcium scoring, 4.1 mSv (IQR, 2.6-6.1 mSv) for coronary CTA, 7.4 mSv (IQR, 6.2-8.5 mSv) for SPECT, and 4.1 mSv (IQR, 2.5-6.8 mSv) for ICA. After 5 years, total per-participant cumulative dose was higher in the CT group (median, 8.1 mSv; IQR, 5.5-12.4 mSv) compared with standard-care group (median, 0 mSv; IQR, 0-4.5 mSv; P < .001). In participants who underwent any imaging, cumulative radiation exposure was higher in the CT group (n = 1345; median, 8.6 mSv; IQR, 6.1-13.3 mSv) compared with standard-care group (n = 549; median, 6.4 mSv; IQR, 3.4-9.2 mSv; P < .001). Conclusion In the SCOT-HEART trial, the 5-year cumulative radiation dose from cardiac imaging was higher in the coronary CT angiography group compared with the standard-care group, largely because of the radiation exposure from CT. Clinical trial registration no. NCT01149590 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dodd and Bosserdt in this issue.

Development and validation of an LC-MS/MS method for quantification of favipiravir in human plasma.

Favipiravir (FVP) is a broad-spectrum antiviral that selectively inhibits viral RNA-dependent RNA polymerase, first trialled for the treatment of influenza infection. It has been shown to be effective against a number of RNA virus families including arenaviruses, flaviviruses and enteroviruses. Most recently, FVP has been investigated as a potential therapeutic for severe acute respiratory syndrome coronavirus 2 infection. A liquid chromatography tandem mass spectrometry method for the quantification of FVP in human plasma has been developed and validated for use in clinical trials investigating favipiravir as treatment for coronavirus disease-2019. Samples were extracted by protein precipitation using acetonitrile, using 13C, 15N- Favipiravir as internal standard. Elution was performed on a Synergi Polar-RP 150 × 2.1 mm 4 µm column using a gradient mobile phase programme consisting of 0.2% formic acid in water and 0.2% formic acid in methanol. The assay was validated over the range 500-50,000 ng/mL; this method was found to be precise and accurate and recovery of FVP from the matrix was high. Stability experiments confirmed and expanded on the known stability of FVP, including under heat treatment and for a period of 10 months at - 80 °C.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Distinguishing Type 1 from Type 2 Myocardial Infarction by Using CT Coronary Angiography.

Purpose: To determine whether quantitative plaque characterization by using CT coronary angiography (CTCA) can discriminate between type 1 and type 2 myocardial infarction. Materials and Methods: This was a secondary analysis of two prospective studies (ClinicalTrials.gov registration nos. NCT03338504 [2014-2019] and NCT02284191 [2018-2020]) that performed blinded quantitative plaque analysis on findings from CTCA in participants with type 1 myocardial infarction, type 2 myocardial infarction, and chest pain without myocardial infarction. Logistic regression analyses were performed to identify predictors of type 1 myocardial infarction. Results: Overall, 155 participants (mean age, 64 years ± 12 [SD]; 114 men) and 36 participants (mean age, 67 years ± 12; 19 men) had type 1 and type 2 myocardial infarction, respectively, and 136 participants (62 years ± 12; 78 men) had chest pain without myocardial infarction. Participants with type 1 myocardial infarction had greater total (median, 44% [IQR: 35%-50%] vs 35% [IQR: 29%-46%]), noncalcified (39% [IQR: 31%-46%] vs 34% [IQR: 29%-40%]), and low-attenuation (4.15% [IQR: 1.88%-5.79%] vs 1.64% [IQR: 0.89%-2.28%]) plaque burdens (P < .05 for all) than those with type 2. Participants with type 2 myocardial infarction had similar low-attenuation plaque burden to those with chest pain without myocardial infarction (P = .4). Low-attenuation plaque was an independent predictor of type 1 myocardial infarction (adjusted odds ratio, 3.44 [95% CI: 1.84, 6.96]; P < .001), with better discrimination than noncalcified plaque burden and maximal area of coronary stenosis (C statistic, 0.75 [95% CI: 0.67, 0.83] vs 0.62 [95% CI: 0.53, 0.71] and 0.61 [95% CI: 0.51, 0.70] respectively; P ≤ .001 for both). Conclusion: Higher low-attenuation coronary plaque burden in patients with type 1 myocardial infarction may help distinguish these patients from those with type 2 myocardial infarction.Keywords: Ischemia/Infarction, CT Angiography, Quantitative CTClinical trial registration nos. NCT03338504 and NCT02284191 Supplemental material is available for this article. © RSNA, 2022.

72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study.

BACKGROUND: Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants. METHODS: DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4·1 weeks (IQR 4·0-5·1) in the dolutegravir group compared with 12·1 weeks (10·7-13·3) in the efavirenz group (adjusted hazard ratio [HR] 1·93 [95% CI 1·5-2·5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life. INTERPRETATION: Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing. FUNDING: Unitaid.

Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. METHODS: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. RESULTS: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. CONCLUSIONS: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03338504.

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter.

BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183  19 February 2021 ISRCTN reference: 27106947.

Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK.

INTRODUCTION: Existing HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive, blood-free and painless drug delivery, and may improve patient adherence. The objective of this study was to develop a novel physiologically-based pharmacokinetic (PBPK) model to simulate the systemic pharmacokinetics of cabotegravir and rilpivirine MAPs using the intradermal route. METHODS: The developed PBPK models were qualified against observed pharmacokinetic data after intramuscular (IM) and intradermal administration of long-acting nanoformulated rilpivirine to rats, and for IM administration of both drugs to healthy adults. Qualified models were then utilised to estimate suitable MAP characteristics (e.g. nanoformulation dose and release rates) and inform dosing strategies to maintain plasma concentrations above target trough concentrations for the designated dosing interval. RESULTS: PBPK models simulated q4-weekly loading and maintenance doses of 360 mg and 180 mg for long-acting formulated cabotegravir between the release rates of 1 × 10-3-3 × 10-3h-1 and 1 × 10-3-1.5 × 10-3h-1 respectively, for a 70 kg adult. Estimated patch size was 60 cm2 for a 360 mg dose of cabotegravir. For q4-weekly dosing, rilpivirine required a 1080 mg loading dose and a 540 mg maintenance dose with release rates of 1.5 × 10-3-2.5 × 10-3h-1 and 5 × 10-4-1 × 10-3h-1, respectively. Weekly dosing was also evaluated to assess the potential application from a smaller patch size. The ability to self-administer via a patch that is only left in place for a short duration makes longer durations less important than for some other long-acting approaches. Weekly cabotegravir required 60 mg between release rates 7 × 10-3-9 × 10-3h-1 and rilpivirine required 270 mg and 180 mg respectively between release rates of 7 × 10-3-9 × 10-3h-1. DISCUSSION: This model estimated optimal dose and release rates for cabotegravir and rilpivirine MAPs. Our approach provides a computational platform to support rational development of intradermal administration strategies to tackle problems associated with chronic oral ARV administration.

Meta-analysis of the effect of CYP2B6, CYP2A6, UGT2B7 and CAR polymorphisms on efavirenz plasma concentrations.

BACKGROUND: Efavirenz primary metabolism is catalysed by CYP2B6 with minor involvement of CYP2A6. Subsequently, phase I metabolites are conjugated by UGT2B7, and constitutive androstane receptor (CAR) has been shown to transcriptionally regulate many relevant enzymes and transporters. Several polymorphisms occurring in the genes coding for these proteins have been shown to impact efavirenz pharmacokinetics in some but not all studies. OBJECTIVES: A meta-analysis was performed to assess the overall effect of CYP2B6 rs3745274, CYP2A6 (rs28399454, rs8192726 and rs28399433), UGT2B7 (rs28365062 and rs7439366) and NR1I3 (rs2307424 and rs3003596) polymorphisms on mid-dose efavirenz plasma concentrations. METHODS: Following a literature review, pharmacokinetic parameters were compiled and a meta-analysis for these variants was performed using Review Manager and OpenMetaAnalyst. A total of 28 studies were included. RESULTS: Unsurprisingly, the analysis confirmed that individuals homozygous for the T allele for CYP2B6 rs3745274 had significantly higher efavirenz concentrations than those homozygous for the G allele [weighted standard mean difference (WSMD) = 2.98; 95% CI 2.19-3.76; P < 0.00001]. A subgroup analysis confirmed ethnic differences in frequency but with a similar effect size in each ethnic group (P = 0.96). Associations with CYP2A6 and UGT2B7 variants were not statistically significant, but T homozygosity for CAR rs2307424 was associated with significantly lower efavirenz concentrations than in C homozygotes (WSMD = -0.32; 95% CI -0.59 to -0.06; P = 0.02). CONCLUSIONS: This meta-analysis provides the overall effect size for the impact of CYP2B6 rs3745274 and NR1I3 rs2307424 on efavirenz pharmacokinetics. The analysis also indicates that some previous associations were not significant when interrogated across studies.

Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine.

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.).

Predicting Drug-Drug Interactions Between Rifampicin and Long-Acting Cabotegravir and Rilpivirine Using Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Cabotegravir and rilpivirine are 2 long-acting (LA) antiretrovirals that can be administered intramuscularly; their interaction with rifampicin, a first-line antituberculosis agent, has not been investigated. The aim of this study was to simulate and predict drug-drug interactions (DDIs) between these LA antiretroviral agents and rifampicin using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The designed PBPK models were qualified (according to European Medicines Agency guidelines) against observed data for oral formulations of cabotegravir, rilpivirine, and rifampicin. Induction potential of rifampicin was also qualified by comparing the DDI between oral cabotegravir and oral rilpivirine with rifampicin. Qualified PBPK models were utilized for pharmacokinetic prediction of DDIs. RESULTS: PBPK models predicted a reduction in both area under the curve (AUC0-28 days) and trough concentration (Ctrough, 28th day) of LA cabotegravir of 41%-46% for the first maintenance dose coadministered with 600 mg once-daily oral rifampicin. Rilpivirine concentrations were predicted to decrease by 82% for both AUC0-28 days and Ctrough, 28th day following the first maintenance dose when coadministered with rifampicin. CONCLUSIONS: The developed PBPK models predicted the theoretical effect of rifampicin on cabotegravir and rilpivirine LA intramuscular formulations. According to these simulations, it is likely that coadministration of rifampicin with these LA formulations will result in subtherapeutic concentrations of both drugs.

Inhibitory Effects of Commonly Used Excipients on P-Glycoprotein in Vitro.

Pharmaceutical excipients are no longer considered inert and have been shown to influence the activity of metabolic enzymes and transporters, resulting in altered pharmacokinetics of substrate drugs. In this study, the effect of 25 excipients commonly used in drug formulations were investigated for their effect on P-glycoprotein (P-gp) activity. The effect of excipients on P-gp were assessed by measuring the change in the cellular accumulation of a P-gp substrate, digoxin, in MDCK-MDR1 (Madin Darby canine kidney transfected with multidrug resistance 1 gene) cells. The cells were exposed to low (10 µM) and high (200 µM) concentrations of excipient along with 10 µM digoxin. Excipient concentrations were chosen to span the range of concentrations previously used for investigating activities in vitro. At 10 µM of excipient, an increase in the intracellular digoxin concentration was seen with d-α-tocopherol poly-(ethylene glycol) succinate (Vit-E-PEG; p = 0.002), poly(ethylene oxide)20 sorbitan monooleate (Tween 80; p = 0.001), cetyltrimethylammonium bromide (CTAB; p = 0.021), poly(ethylene oxide)35 modified castor oil (Cremophor EL; p = 0.01), polyethylene glycol15-hydroxystearate (Solutol HS 15; p = 0.006), and poly(ethylene glycol) hexadecyl ether (Brij 58; p = 0.001). At 200 µM, Vit-E-PEG ( p < 0.0001), sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT; p < 0.0001), Tween 80 ( p < 0.0001), CTAB ( p = 0.004), poly(ethylene oxide)20 sorbitan monolaurate (Tween 20; p < 0.0001), Cremophor EL ( p < 0.0001), Solutol HS 15 ( p < 0.0001), Brij 58 ( p < 0.0001), and sodium carboxymethyl cellulose (NaCMC; p = 0.006) increased intracellular digoxin significantly. Concentration-dependent inhibition of P-gp was then investigated for selected excipients giving an IC50 for Vit-E-PEG (12.48 µM), AOT (192.5 µM), Tween 80 (45.29 µM), CTAB (96.67 µM), Tween 20 (74.15 µM), Cremophor EL (11.92 µM), Solutol HS 15 (179.8 µM), Brij 58 (25.22 µM), and NaCMC (46.69 µM). These data add to the growing body of evidence demonstrating that not all excipients are inert and will aid excipient choice for rational formulation development.

Effect of intermittent rifampicin on the pharmacokinetics and safety of raltegravir.

OBJECTIVES: Previous studies of raltegravir and rifampicin have not studied the interaction when rifampicin is dosed intermittently. This study aimed to assess the pharmacokinetics of twice daily raltegravir and intermittently dosed rifampicin. METHODS: This was a prospective, open, single-arm, three-part, controlled study in healthy volunteers. Over a period of 38 days subjects received 5 days of standard-dose raltegravir (400 mg twice daily) followed by 28 days of standard-dose raltegravir plus rifampicin three times a week followed by 5 days of high-dose (800 mg twice daily) raltegravir plus rifampicin three times a week. Pharmacokinetic sampling was performed on days 5, 33 and 38. Raltegravir pharmacokinetic parameters were determined by non-compartmental analysis and reported as geometric means and 90% CIs. ClinicalTrials.gov: NCT01424826. RESULTS: Sixteen subjects (12 females) completed the study. Raltegravir trough plasma concentration (C12) was significantly lower in the presence of rifampicin when dosed at 400 mg twice daily (40%), which was not observed with 800 mg twice daily dosing. Raltegravir Cmax and AUC0-12 were both significantly higher in the presence of rifampicin when dosed at 800 mg twice daily (76% and 84%, respectively), but this dose was well tolerated. CONCLUSIONS: This study suggests that rifampicin induction of raltegravir is comparable between daily and intermittent rifampicin. In the absence of definitive clinical efficacy data to suggest otherwise, doses of 800 mg of raltegravir twice daily with rifampicin thrice weekly are well tolerated and yield higher AUCs and comparable C12 when compared with raltegravir alone.