Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults.

BACKGROUND: Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine. METHODS: Two single-center, phase 1, open-label, randomized bioequivalence studies were conducted in healthy adult non-smokers, aged 18-55 years. One study compared the rate and extent of absorption of the marketed formulation of rimegepant 75 mg orally disintegrating tablet (ODT) administered sublingually with rimegepant 75 mg oral tablet, an earlier development formulation; the second compared the rate and extent of absorption of 75 mg rimegepant ODT administered supralingually with rimegepant oral tablet. RESULTS: The ln-transformed geometric mean ratios for the area under the curve (AUC) from time 0 to the last available concentration time point (time t) (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and maximum observed concentration (Cmax) of sublingual rimegepant ODT vs. rimegepant tablet were 97, 97, and 105%, respectively, and the 90% confidence intervals (CIs) were all within the predefined range (80-125%) for bioequivalence. The ln-transformed geometric mean ratios for the AUC0-t and AUC0-inf of supralingual rimegepant ODT vs. rimegepant tablet were 98%, the 90% CIs were within the predefined range (80-125%), and the geometric mean ratio for Cmax was 103% with the 95% upper confidence bound for the scaled average bioequivalence criterion of -0.0575 (within-participant coefficient of variation for the reference for Cmax > 30%) for bioequivalence. CONCLUSIONS: Rimegepant 75 mg ODT, administered sublingually or supralingually, and rimegepant 75 mg oral tablet were bioequivalent.

The time-course of real-world scene perception: Spatial and semantic processing.

Real-world scene perception unfolds remarkably quickly, yet the underlying visual processes are poorly understood. Space-centered theory maintains that a scene's spatial structure (e.g., openness, mean depth) can be rapidly recovered from low-level image statistics. In turn, the statistical relationship between a scene's spatial properties and semantic content allows for semantic identity to be inferred from its layout. We tested this theory by investigating (1) the temporal dynamics of spatial and semantic perception in real-world scenes, and (2) dependencies between spatial and semantic judgments. Participants viewed backward-masked images for 13.3 to 106.7 ms, and identified the semantic (e.g., beach, road) or spatial structure (e.g., open, closed-off) category. We found no temporal precedence of spatial discrimination relative to semantic discrimination. Computational analyses further suggest that, instead of using spatial layout to infer semantic categories, humans exploit semantic information to discriminate spatial structure categories. These findings challenge traditional 'bottom-up' views of scene perception.

The Effect of Antiseizure Medication Administration on Mortality and Early Posttraumatic Seizures in Critically Ill Older Adults with Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Older adults represent an understudied and growing TBI population. Current Brain Trauma Foundation guidelines support prophylactic antiseizure medication (ASM) administration to reduce the risk of early posttraumatic seizures (within 7 days of injury) in patients with severe TBI. Whether ASM decreases mortality or early seizure risk in this population remains unclear. This study addresses the knowledge gap regarding the impact of ASM administration on the risk of seizure or mortality after TBI in patients more than 65 years of age. METHODS: This retrospective cohort study used a publicly available data set from the Medical Information Mart for Intensive Care-III from the Massachusetts Institute of Technology. Our cohort included patients 65 years or older with a primary exposure of early ASM administration with TBI resulting in an intensive care unit (ICU) admission in a level I trauma center from 2001 to 2012. A double-robust inverse propensity scale weighted model on the basis of proportional hazard and logistic regression models was created to assess the association between ASM administration and risk of death within 7 days of admission to the ICU. Secondary outcomes included 30-day mortality and 1-year mortality, early posttraumatic seizures, ICU length of stay, and hospital length of stay. RESULTS: Of 1145 patients 65 years or older with TBI admitted to an ICU, 783 (68.4%) received ASM within the first 24 h. Patients meeting inclusion criteria were predominantly white (83.8%) and were male (52.3%), with a median (interquartile range) age of 81 (74-86) years. TBI severity, classified by Glasgow Coma Score, was predominantly mild (71.2%), followed by moderate (16.8%) and severe (11.3%). Patients who received ASM were less likely to have died at 7 days (adjusted death hazard ratio [HR] = 0.48 [95% confidence interval {CI} 0.28-0.88], P = 0.005), at 30 days (adjusted HR 0.67 [95% CI 0.45-0.99], P = 0.045), and at 1 year (adjusted HR 0.72 [95% CI 0.54-0.97], P = 0.029). Groups were not different in regard to seizure (adjusted seizure odds ratio 1.18 [95% CI 0.61-2.26]) compared with those who did not receive ASM. CONCLUSIONS: Early ASM administration was associated with reduced mortality at 7 days, 30 days, and 1 year but did not decrease the risk of early seizures among older adults who presented with TBI at an ICU. This benefit was observed in mild, moderate, and severe TBI assessed by Glasgow Coma Score on presentation among patients 65 years old and older and suggests broader recommendations for the use of ASM in older adults who present with TBI of any severity at an ICU.

P-Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects.

Rimegepant (Nurtec ODT)-an orally administered, small-molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine-is a substrate for both the P-glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single-center, open-label, randomized study was conducted in 2 parts, both of which were 2-period, 2-sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200-mg cyclosporine, a strong inhibitor of the P-glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600-mg quinidine, a strong selective P-glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49-1.72) and 1.41 (1.27-1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40-1.72) and 1.67 (1.46-1.91), respectively, versus rimegepant alone. Strong P-glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2-fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure.

Human Milk and Plasma Pharmacokinetics of Single-Dose Rimegepant 75 mg in Healthy Lactating Women.

Objective: Investigate whether rimegepant-an oral small molecule calcitonin gene-related peptide receptor antagonist for the treatment of migraine-is excreted in human milk after a single 75 mg dose and characterize its concentration-time profile in the plasma and milk of healthy lactating women to determine the relative infant dose (RID). Methods: This open-label, single-center study enrolled healthy lactating women aged 18-40 years with a gestation of 37-42 weeks and uncomplicated delivery of a single healthy child ≥2 weeks (14 days) and ≤6 months before study drug administration. Plasma samples were collected 0, 1, 2, 4, and 8 hours postdose; human milk samples were collected at 0, 1, 2, 4, 8, 12, 16, 24, 32, and 36 hours. The milk:plasma drug concentration ratio was estimated as the ratio of the human milk:plasma areas under the curve. The RID (%) was calculated as 100 times the quotient of the body weight-normalized infant and maternal doses. Results: Subjects (N = 12) were enrolled between 25 January and 15 September 2020. The mean (standard deviation [SD]) age was 29.8 (3.6) years; mean (SD) body mass index was 26.8 (4.9) kg/m2. The mean (SD) RID of rimegepant was 0.51% (0.14). The mean (SD) body-weight normalized infant dose was 0.005 (0.001) mg/kg/day, the mean (SD) body-weight normalized maternal dose was 1.04 (0.18) mg/kg/day, and mean (SD) maternal body weight was 74.0 (13.3) kg. Conclusion: On a weight-adjusted basis, the mean RID of rimegepant was <1% of the maternal dose.

The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Category systems for real-world scenes.

Categorization performance is a popular metric of scene recognition and understanding in behavioral and computational research. However, categorical constructs and their labels can be somewhat arbitrary. Derived from exhaustive vocabularies of place names (e.g., Deng et al., 2009), or the judgements of small groups of researchers (e.g., Fei-Fei, Iyer, Koch, & Perona, 2007), these categories may not correspond with human-preferred taxonomies. Here, we propose clustering by increasing the rand index via coordinate ascent (CIRCA): an unsupervised, data-driven clustering method for deriving ground-truth scene categories. In Experiment 1, human participants organized 80 stereoscopic images of outdoor scenes from the Southampton-York Natural Scenes (SYNS) dataset (Adams et al., 2016) into discrete categories. In separate tasks, images were grouped according to i) semantic content, ii) three-dimensional spatial structure, or iii) two-dimensional image appearance. Participants provided text labels for each group. Using the CIRCA method, we determined the most representative category structure and then derived category labels for each task/dimension. In Experiment 2, we found that these categories generalized well to a larger set of SYNS images, and new observers. In Experiment 3, we tested the relationship between our category systems and the spatial envelope model (Oliva & Torralba, 2001). Finally, in Experiment 4, we validated CIRCA on a larger, independent dataset of same-different category judgements. The derived category systems outperformed the SUN taxonomy (Xiao, Hays, Ehinger, Oliva, & Torralba, 2010) and an alternative clustering method (Greene, 2019). In summary, we believe this novel categorization method can be applied to a wide range of datasets to derive optimal categorical groupings and labels from psychophysical judgements of stimulus similarity.

A Pharmacokinetic Bioequivalence Study Comparing Sublingual Riluzole (BHV-0223) and Oral Tablet Formulation of Riluzole in Healthy Volunteers.

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV-0223 is a Zydis-based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40-mg BHV-0223 and standard 50-mg oral riluzole tablets, and the food effect on BHV-0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV-0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration-time curve (AUC) from time zero to time of last nonzero concentration (AUC0-t ) (89.9%; confidence interval [CI], 87.3%-92.5%), AUC from time zero to infinity (AUC0-∞ ) (89.8%; CI, 87.3%-92.4%), and maximum observed concentration (112.7%; CI, 105.5%-120.4%) all met bioequivalence criteria (80%-125%). Subsequently, 67 subjects received BHV-0223 under fed conditions. The geometric mean ratios of AUC0-t (91.2%; CI, 88.1-94.3%), and AUC0-∞ (92.0%; CI, 89.0-95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV-0223 was well tolerated. This study demonstrated that 40-mg sublingual BHV-0223 is bioequivalent to 50-mg oral riluzole tablets.

No meaningful drug interactions with doravirine, lamivudine and tenofovir disoproxil fumarate coadministration.

BACKGROUND: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with coadministration. METHODS: Two trials were conducted. Study 1: two-period, fixed-sequence; eight healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, coadministration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC 300 mg + TDF 300 mg; ≥7-day washout between periods. RESULTS: Study 1: geometric mean ratios (GMRs; 90% confidence interval [CI]) of DOR area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and observed plasma concentrations at 24 h post-dose (C24 h; DOR+TDF/DOR) were 0.95 (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. Study 2: GMRs (90% CI) of DOR AUC0-∞ and C24 h (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and tenofovir AUC0-∞ (DOR+3TC+TDF/3TC+TDF) were 0.94 (0.88, 1.00) and 1.11 (0.97, 1.28), respectively. Study drugs were generally well tolerated. CONCLUSIONS: Multiple doses of TDF did not have a clinically meaningful effect on DOR PK. The PK of DOR were similar when administered alone or in combination with 3TC and TDF. DOR had no meaningful effect on the PK of 3TC and tenofovir.

Disruptive coloration and binocular disparity: breaking camouflage.

Many species employ camouflage to disguise their true shape and avoid detection or recognition. Disruptive coloration is a form of camouflage in which high-contrast patterns obscure internal features or break up an animal's outline. In particular, edge enhancement creates illusory, or 'fake' depth edges within the animal's body. Disruptive coloration often co-occurs with background matching, and together, these strategies make it difficult for an observer to visually segment an animal from its background. However, stereoscopic vision could provide a critical advantage in the arms race between perception and camouflage: the depth information provided by binocular disparities reveals the true three-dimensional layout of a scene, and might, therefore, help an observer to overcome the effects of disruptive coloration. Human observers located snake targets embedded in leafy backgrounds. We analysed performance (response time) as a function of edge enhancement, illumination conditions and the availability of binocular depth cues. We confirm that edge enhancement contributes to effective camouflage: observers were slower to find snakes whose patterning contains 'fake' depth edges. Importantly, however, this effect disappeared when binocular depth cues were available. Illumination also affected detection: under directional illumination, where both the leaves and snake produced strong cast shadows, snake targets were localized more quickly than in scenes rendered under ambient illumination. In summary, we show that illusory depth edges, created via disruptive coloration, help to conceal targets from human observers. However, cast shadows and binocular depth information improve detection by providing information about the true three-dimensional structure of a scene. Importantly, the strong interaction between disparity and edge enhancement suggests that stereoscopic vision has a critical role in breaking camouflage, enabling the observer to overcome the disruptive effects of edge enhancement.

Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions.

Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.

Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans.

Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, ∼200 µCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [14 C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.

No Pharmacokinetic Drug-Drug Interaction Between Prasugrel and Vorapaxar Following Multiple-Dose Administration in Healthy Volunteers.

Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design. In sequence 1, 36 subjects received prasugrel 60 mg on day 1 and then prasugrel 10 mg once daily on days 2 to 7, followed by vorapaxar 40 mg and prasugrel 10 mg on day 8 and then vorapaxar 2.5 mg and prasugrel 10 mg orally once daily on days 9 to 28. In sequence 2, 18 subjects received vorapaxar 40 mg on day 1 and then vorapaxar 2.5 mg once daily on days 2 to 21. The geometric mean ratios (90% confidence intervals) for AUCτ and Cmax of coadministration/monotherapy for vorapaxar (0.93 ng·h/mL[0.85-1.02 ng·h/mL] and 0.95 ng/mL [0.86-1.05 ng/mL]) and R-138727 (0.91 ng·h/mL [0.85- 0.99 ng·h/mL] and 1.02 ng/mL [0.89-1.17 ng/mL]) were within prespecified bounds, demonstrating the absence of a pharmacokinetic interaction between vorapaxar and prasugrel. There was no specific safety or tolerability risk associated with multiple-dose coadministration of vorapaxar and prasugrel. In conclusion, in this study in healthy volunteers, there was no pharmacokinetic drug-drug interaction between vorapaxar and prasugrel. Multiple-dose coadministration of the 2 drugs was generally well tolerated.

The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co-administration of single and multiple doses of rifampin on doravirine pharmacokinetics. METHODS: In period 1 of this open-label, two-period, fixed-sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4-18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements. RESULTS: Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78-1.06) and 0.90 (0.80-1.01), respectively. Doravirine maximum plasma concentration increased when co-administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21-1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10-0.15), plasma concentration at 24 h post-dose: 0.03 (0.02-0.04), maximum plasma concentration: 0.43 (0.35-0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion. CONCLUSIONS: Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co-administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy.

A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir.

INTRODUCTION: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed. METHODS: Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23-42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations. RESULTS: The steady-state concentration 24 h post-dose (C24) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration-time curve from dosing to 24 h post-dose (AUC0-24), maximum concentration (C max), and C24 geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC0-24, C24, and C max, respectively). Both drugs were generally well tolerated. CONCLUSION: The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.

A randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naive HIV-infected individuals.

OBJECTIVE: To assess the antiviral activity, pharmacokinetics, and safety of doravirine in nonnucleoside reverse transcriptase inhibitor-naïve, HIV-infected men. DESIGN: Double-blind, randomized, two-panel, dose-escalation study. METHODS: In two sequential panels, 18 individuals received doravirine [25 mg (Panel A) or 200 mg (Panel B)] or matching placebo once daily for 7 days. Plasma samples were collected daily for measurement of HIV-1 RNA levels and doravirine pharmacokinetics. RESULTS: For the mean change from baseline in HIV RNA (log10 copies/ml) at 24 h after the day 7 dose, the mean difference (90% confidence interval) between doravirine and placebo was -1.37 (-1.60, -1.14) in the 25-mg group and -1.26 (-1.51, -1.02) in the 200-mg group. None of the participants had viral breakthrough. Increases in mean AUC0-24 h, Cmax, and C24 h were slightly less than dose-proportional, with median Tmax of 1.0-2.0 h. Steady state was achieved after 3-5 days of once-daily dosing. At steady state, accumulation ratios (day 7/day 1) for AUC0-24 h, Cmax, and C24 h were 1.2-1.6. The calculated effective t1/2 (10-16 h) was similar to that in HIV-uninfected individuals. Adverse events were limited in number, transient, and generally mild to moderate in intensity. One participant had a serious adverse event of elevated liver enzymes (judged probably not drug related) in concurrence with a newly acquired hepatitis C infection. CONCLUSION: Doravirine monotherapy demonstrated robust antiviral activity at both dose levels, without evidence of viral resistance, and was generally well tolerated. Doravirine pharmacokinetics in HIV-infected individuals were similar to those in uninfected individuals receiving similar doses in prior studies.

Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects.

BACKGROUND: Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug-drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. METHODS: The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6-1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30-750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). RESULTS: The maximum plasma concentration (Cmax) of doravirine was achieved within 1-5 h with an apparent terminal half-life of 12-21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7 days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1-1.5 in the area under the plasma concentration-time curve during the dosing interval (AUC0-24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0-∞) and C24 h with no change in Cmax. Midazolam AUC0-∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. CONCLUSIONS: Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.