Medications in Patients with Dementia and Behavioral Disturbance.

BACKGROUND: Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population. OBJECTIVE: To describe real-world medications use in this population. METHODS: A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015-Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. RESULTS: A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23%to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). A list of 60 unique medications were suggested to be the commonly used drugs in dementia patients with BD. CONCLUSION: In dementia patients with BD, anti-dementia medications, antidepressants, anticonvulsants, hypnotics and antipsychotics were the most used drug classes. Antidepressants and antipsychotics use were more frequent after a BD event, which suggests a need for safe drugs targeting BD in dementia patients.

Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin.

Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4-fold, M9 exposure is increased by only 1.2-fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4-fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug-Drug Interactions.

Doravirine (MK-1439) is a novel non-nucleoside reverse transcriptase inhibitor indicated for the combination treatment of human immunodeficiency virus type-1 (HIV-1) infection. The recommended dose is 100 mg once daily. This review summarizes the pharmacokinetics of doravirine, the influence of intrinsic factors, and its drug-drug interaction (DDI) profile. Following oral administration, doravirine is rapidly absorbed (median time to maximum plasma concentration, 1-4 h) and undergoes cytochrome P450 (CYP)3A-mediated oxidative metabolism. Steady-state geometric means for AUC0-24, C24, and Cmax in individuals with HIV-1 following administration of doravirine 100 mg once daily are 37.8 µM·h, 930 nM, and 2260 nM, respectively. Age, gender, severe renal impairment, and moderate hepatic impairment have no clinically meaningful effect on doravirine pharmacokinetics, and there is limited potential for DDIs. No dose adjustment is necessary when doravirine is co-administered with strong CYP3A inhibitors. However, doravirine is contraindicated with strong CYP3A inducers (e.g., rifampin), and dose adjustment of doravirine is recommended for co-administration with the moderate CYP3A inducer, rifabutin. Included in this review are clinical trial data from phase I pharmacokinetic trials, including DDI trials and trials in participants with renal and hepatic disease but without HIV-1 infection (N = 326), as well as phase I, II, and III safety and efficacy trials in participants living with HIV-1 (N = 991). Based on these data, the pharmacokinetic profile of doravirine supports its use in diverse populations living with HIV-1 and allows co-administration with various antiretroviral agents and treatments for commonly occurring co-morbidities.

Pharmacokinetics, safety and tolerability of long-acting parenteral intramuscular injection formulations of doravirine.

WHAT IS KNOWN AND OBJECTIVE: Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection. METHODS: After confirmation of tolerability and safety of oral doravirine, 36 participants were randomized 1:1:1 to receive IM doravirine 200 mg as Treatment A (1 × 1 mL, 20% [200 mg/mL] suspension), B (1 × 0.66 mL, 30% [300 mg/mL] suspension) or C (2 × 0.5 mL, 20% suspension). Blood samples were taken as venous plasma, venous dried blood spots (DBS) and fingerstick DBS. RESULTS AND DISCUSSION: Plasma concentration-time profiles following IM treatments demonstrated rapid initial doravirine release, with initial peak ~4 days post-injection, followed by decline over the next ~6 days; a second peak was reached at ~24-36 days, corresponding to prolonged and sustained release, with measurable concentrations up to Day 183. Treatment C was associated with highest peak concentrations and shortest time to maximum concentration. Elimination half-lives for all IM formulations were prolonged versus oral administration (~46-58 days vs ~11-15 hours). Oral doravirine and IM doravirine were generally well tolerated; injection-site pain was the most common adverse event for IM doravirine. Doravirine concentrations from DBS samples showed strong correlations to venous plasma concentrations. WHAT IS NEW AND CONCLUSIONS: Novel doravirine LAP IM injection formulations investigated in this study demonstrated sustained plasma doravirine concentrations over a course of >20 weeks.

Comparative Bioavailability of Oral Granule Formulations of the HIV Antiretroviral Drugs Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate.

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.

Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor indicated for the treatment of HIV type 1 infection. A subset of people living with HIV receives methadone for the treatment of opioid addiction. The current study (NCT02715700) was an open-label, multiple-dose, drug interaction study in participants on a methadone maintenance program to investigate potential drug-drug interactions between doravirine and methadone. Participants received a stable methadone maintenance dose of 20 to 180 mg once daily for 14 days prior to day 1 and remained on their maintenance dose over days 1 through 7. On days 2 through 6, an oral dose of doravirine 100 mg was coadministered. For doravirine and methadone pharmacokinetic analysis, blood samples were collected before dosing through 24 hours after dosing. Fourteen participants were enrolled; all participants completed the study. For R-methadone, geometric least squares mean ratios (90% confidence intervals) for dose-normalized area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration ([methadone + doravirine]/methadone alone) were 0.95 (0.90-1.01), 0.95 (0.88-1.03), and 0.98 (0.93-1.03), respectively. For doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone; geometric least squares mean ratios ([methadone + doravirine]/doravirine alone [90% confidence intervals]) were 0.74 (0.61-0.90), 0.80 (0.63-1.03), and 0.76 (0.63-0.91), respectively. Coadministration of doravirine and methadone was generally well tolerated. No serious adverse events occurred, and there were no discontinuations. In conclusion, coadministration of methadone and doravirine did not have a clinically meaningful effect on the pharmacokinetic profile of either agent.

Evaluation of the Pharmacokinetics of Metformin Following Coadministration With Doravirine in Healthy Volunteers.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, type 2 diabetes mellitus is often treated with metformin. Perturbations of metformin absorption or elimination may affect its safety and efficacy profile; therefore, understanding potential drug-drug interactions between doravirine and metformin is important. An open-label, fixed-sequence, 2-period trial in healthy adults was conducted. Single-dose metformin 1000 mg was administered in period 1; in period 2, doravirine 100 mg was administered once daily on days 1 to 7, and single-dose metformin 1000 mg was administered on day 5. Plasma pharmacokinetics for metformin alone and coadministered with doravirine were assessed. Fourteen participants enrolled and completed the trial. Least-squares geometric mean ratios and 90% confidence intervals of metformin AUC0-∞ , and Cmax following coadministration of metformin and doravirine compared with metformin alone were 0.94 (0.88-1.00) and 0.94 (0.86-1.03), respectively; metformin Tmax and half-life were also minimally impacted. These data indicate that doravirine did not have a clinically relevant effect on the pharmacokinetics of metformin. Metformin alone and coadministered with doravirine was generally well tolerated. These data support coadministration of doravirine 100 mg and metformin 1000 mg without dose adjustment.

A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid-Reducing Agents.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus type 1 infection. Because of potential concomitant administration with acid-reducing agents, a drug-interaction trial was conducted to evaluate the potential impact of these types of medications on doravirine pharmacokinetics. In an open-label, 3-period, fixed-sequence trial, healthy adult participants received the following: period 1, a single dose of doravirine 100 mg; period 2, coadministration of a single dose of doravirine 100 mg and an antacid (1600 mg aluminum hydroxide, 1600 mg magnesium hydroxide, and 160 mg simethicone); period 3, 40 mg pantoprazole once daily on days 1-5 coadministered with a single dose of doravirine 100 mg on day 5. There was a minimum 10-day washout between periods. Plasma samples for pharmacokinetic evaluation were collected, and safety was assessed. Fourteen participants (8 male, 6 female) were enrolled, and 13 completed the trial. Geometric mean ratios (90% confidence intervals) for doravirine AUC0-inf , Cmax , and C24 for doravirine + antacid/doravirine were 1.01 (0.92-1.11), 0.86 (0.74-1.01), and 1.03 (0.94-1.12), respectively, and for doravirine + pantoprazole/doravirine were 0.83 (0.76-0.91), 0.88 (0.76-1.01), and 0.84 (0.77-0.92), respectively. Doravirine was generally well tolerated administered alone or with either of the acid-reducing agents. Coadministration of an aluminum/magnesium-containing antacid or pantoprazole did not have a clinically meaningful effect on doravirine pharmacokinetics, supporting the use of acid-reducing agents with doravirine.

Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir.

Doravirine is a non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Due to the high prevalence of HIV-1 and hepatitis C virus (HCV) coinfection and coadministration of HIV-1 and HCV treatment, potential drug-drug interactions (DDIs) between doravirine and two HCV treatments were investigated in two phase 1 drug interaction trials in healthy participants. Trial 1 investigated the effect of multiple-dose doravirine and elbasvir + grazoprevir coadministration (N = 12), and trial 2 investigated the effect of single-dose doravirine and ledipasvir-sofosbuvir coadministration (N = 14). Doravirine had no clinically relevant effect on the pharmacokinetics of elbasvir, grazoprevir, ledipasvir, sofosbuvir, or the sofosbuvir metabolite GS-331007. Coadministration of elbasvir + grazoprevir with doravirine moderately increased doravirine area under the concentration-time curve from 0 to 24 h (AUC0-24), maximal concentration (Cmax), and concentration 24 h postdose (C24), with geometric least-squares mean ratio (GMR) with 90% confidence intervals (CI) of 1.56 (1.45, 1.68), 1.41 (1.25, 1.58), and 1.61 (1.45, 1.79), respectively. Doravirine AUC0-∞, Cmax, and C24 values increased slightly following coadministration with ledipasvir-sofosbuvir (GMR [90% CI] of 1.15 [1.07, 1.24], 1.11 [0.97, 1.27], and 1.24 [1.13, 1.36], respectively). The modest increases in doravirine exposure are not clinically meaningful based on the therapeutic profile of doravirine. Effects are likely secondary to cytochrome P450 3A and P-glycoprotein inhibition by grazoprevir and ledipasvir, respectively. Coadministration of doravirine with elbasvir + grazoprevir or ledipasvir-sofosbuvir was generally well tolerated. Clinically relevant DDIs are not expected to occur between doravirine and elbasvir-grazoprevir or ledipasvir-sofosbuvir at the therapeutic doses.

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.

Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis.

AIMS: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. METHODS: This was an open-label, fixed-sequence, two-period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7-day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), were assessed. RESULTS: Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL-6 or hs-CRP. Treatment with tildrakizumab was generally well tolerated. CONCLUSION: In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug-drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti-inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0-∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.).

Multiple Doses of Rifabutin Reduce Exposure of Doravirine in Healthy Subjects.

Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretroviral therapies. The cytochrome P450 (CYP)3A-dependent metabolism of doravirine makes it susceptible to interactions with modulators of this pathway, including the antituberculosis treatment rifampin. Rifabutin, an alternative antibiotic used to treat tuberculosis, may have a lower-magnitude effect on CYP3A. The aim of this trial was to determine the effect of steady-state rifabutin on doravirine single-dose pharmacokinetics and tolerability. In this open-label, 2-period, fixed-sequence, drug-drug interaction study, healthy subjects received a single dose of doravirine 100 mg alone and coadministered on day 14 of once-daily administration of rifabutin 300 mg for 16 days. Plasma samples were taken to determine doravirine pharmacokinetics, and safety was monitored throughout. Dose adjustment of doravirine in the presence of coadministered rifabutin was explored through nonparametric superposition analysis. Rifabutin reduced doravirine area under the concentration-time curve from time zero to infinite and plasma drug concentration 24 hours postdose with geometric mean ratios ([rifabutin+doravirine]/[doravirine alone]) (90%CIs) of 0.50 (0.45-0.55) and 0.32 (0.28-0.35), respectively. Doravirine apparent clearance increased from 5.9 L/h without rifabutin to 12.2 L/h when coadministered. Doravirine pharmacokinetics with and without coadministered rifabutin were not equivalent. Nonparametric superposition analysis projected that administration of doravirine 100 mg twice daily with rifabutin will restore steady-state trough concentration values to efficacious levels associated with doravirine 100 mg once daily in the absence of CYP3A inducers. Doravirine may be coadministered with rifabutin when the doravirine dose frequency is increased from 100 mg once daily to 100 mg twice daily.

Pharmacokinetics of Tildrakizumab (MK-3222), an Anti-IL-23 Monoclonal Antibody, After Intravenous or Subcutaneous Administration in Healthy Subjects.

Tildrakizumab, a high-affinity humanized IgG1k antibody that selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function, is under investigation for treatment of moderate-to-severe chronic plaque psoriasis. The objective of this analysis was to assess the pharmacokinetics, bioavailability and safety/tolerability of single ascending doses of tildrakizumab after intravenous (IV) and subcutaneous (SC) dosing in healthy subjects. P05661 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab IV doses of 0.1, 0.5, 3 and 10 mg/kg, or placebo. P05776 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab SC doses of 50 or 200 mg, or placebo. After either single IV or SC dosing, tildrakizumab exhibited slow systemic clearance (CL), limited volume of distribution and a long t1/2 . Both the Cmax and the area under the curve (AUC) increased proportionally with doses from 0.1 to 10 mg/kg, or 50-200 mg. The bioavailability of SC dosing was ~80% (90% CI: 62-103%) for 50 mg and ~73% (90% CI: 46-115%) for 200 mg, respectively, versus 0.5 and 3 mg/kg IV. Across both studies, six of 43 evaluable subjects were positive for post-dose antidrug antibodies; two of these were positive for neutralizing antibodies. Most adverse events (AEs) were mild; the most frequent AEs included upper respiratory tract infection and headache. Single doses of tildrakizumab 0.1, 0.5, 3 and 10 mg/kg administered IV or single doses of 50 and 200 mg administered SC were safe and well tolerated in healthy adult subjects.

A Randomized Trial to Assess the Effect of Doravirine on the QTc Interval Using a Single Supratherapeutic Dose in Healthy Adult Volunteers.

INTRODUCTION: Doravirine is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor exhibiting a robust safety and efficacy profile in combination with other antiretrovirals. While existing data do not suggest that doravirine delays cardiac repolarization, the aim of this trial was to evaluate the effects of a supratherapeutic dose of doravirine on the heart-rate corrected QT (QTc) interval in healthy adults. METHODS: A randomized, three-period, crossover, placebo-controlled trial was conducted in healthy adults, 18-55 years of age. Three treatments were administered: single-dose doravirine 1200 mg, placebo, and positive control (single-dose moxifloxacin 400 mg). QT interval measurements were collected at serial time points following treatment administration. Clinically significant placebo-corrected, baseline-adjusted QTc interval prolongation was defined when the upper bound of the two-sided 90% confidence interval (CI) for the mean effect on double delta QTc exceeded 10 ms. Doravirine tolerability and pharmacokinetics were also evaluated. RESULTS: Forty-five subjects were enrolled and 39 completed the study per protocol. Fridericia's QT correction for heart rate was demonstrated to be inadequate; therefore, a population-specific correction was applied (QTcP). Assay sensitivity was confirmed with moxifloxacin. Following doravirine administration, QTc intervals did not exceed the pre-specified significance threshold - upper 90% CIs were ≤5.42 ms across all time points. Categorical analyses identified no outliers or clinically meaningful deviations. Doravirine geometric mean area under the time-concentration curve from dosing until 24 h post-dose (AUC0-24) and maximum plasma concentration (C max) were 119 µM·h and 9240 nM, respectively, which exceeded values expected following therapeutic dose administration of doravirine 100 mg, even in the setting of intrinsic and extrinsic factors that may cause increases in doravirine concentrations. All treatments were generally well tolerated. CONCLUSION: A single oral supratherapeutic dose of doravirine 1200 mg does not cause clinically meaningful QTc interval prolongation in healthy adults.

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.

Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics.

Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women). Subjects with hepatic impairment were required to have chronic, stable hepatic impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-∞ , 0.93 (0.74-1.18) for AUC0-24 h , 0.90 (0.66-1.24) for Cmax , and 0.99 (0.74-1.33) for C24 h . Geometric mean apparent terminal t½ was ∼18 hours for both groups, whereas median Tmax was 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that moderate hepatic impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and moderate hepatic impairment.

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.