A Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults.

PURPOSE: Patients with chronic cough are typically female and have a mean age of ~ 60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18-55 years) and older (65-80 years) males and females. METHODS: A randomized, double-blind, placebo-controlled study was conducted. Healthy adult participants were stratified into 4 cohorts by age and sex (younger males/females and older males/females) and randomized 4:1 (younger adults) or 3:1 (older adults) to receive gefapixant 300 mg twice daily (BID) for 1 week, followed by gefapixant 600 mg BID for 2 weeks or placebo. Safety, tolerability, and PK were assessed. RESULTS: Of 36 randomized and treated participants, 28 (100%) receiving gefapixant and 6 (75%) receiving placebo reported ≥ 1 adverse event (AE). The most common treatment-related AEs in the gefapixant group were taste related. Predefined renal/urologic AEs were reported by 7 (25%) participants receiving gefapixant (all mild to moderate in severity). Gefapixant exposure was generally lower in younger males compared with younger females and older adults; however, differences may have been due to estimated glomerular filtration rate. CONCLUSION: The safety profile of gefapixant 300-600 mg BID was generally consistent with previous studies. Additional characterization of gefapixant PK as a function of age and sex using population PK modeling is warranted.

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.

Randomized, controlled, proof-of-concept trial of gefapixant for endometriosis-related pain.

OBJECTIVE: To evaluate the P2X3 receptor antagonist, gefapixant, for treating moderate-to-severe endometriosis-related pain. DESIGN: Randomized, double-blind, phase 2, and proof-of-concept trial. SETTING: Outpatients at hospitals, medical centers or clinical research sites. PATIENT(S): Premenopausal women age 18-49 years with moderate-to-severe endometriosis-related pain who were not using hormonal treatment. INTERVENTION(S): Gefapixant (45-mg twice daily) or placebo over two menstrual cycles. MAIN OUTCOME MEASURE(S): Participants rated peak pelvic pain severity daily on a 0 (no pain) - 10 (extremely severe pain) scale. The primary endpoint was change from baseline in average daily peak pelvic pain severity during treatment cycle 2. RESULT(S): All 187 participants randomized (gefapixant, N = 94; placebo, N = 93) took ≥1 dose of investigational treatment and all but six in each treatment group completed the trial. The model-based least-squares mean reduction from baseline in average daily peak pelvic pain severity during treatment cycle 2 was -2.2 for gefapixant and -1.7 for placebo (difference, -0.5; 95% confidence interval, -1.01 to 0.03). In secondary analyses, the difference between gefapixant and placebo in peak pelvic pain severity reduction from baseline on menstrual days was -0.6 (95% confidence interval, -1.18 to -0.06) and -0.5 (95% confidence interval, -1.04 to 0.03) on nonmenstrual days. Taste-related adverse events were reported in 31.9% of participants for gefapixant vs. 4.3% for placebo. Pharmacokinetic assessments at months 1 and 2 clinic visits indicated that of the 94 participants in the gefapixant group, 39 had detectable levels of gefapixant in the blood for both assessments although 38 had no detectable levels for ≥1 assessment. CONCLUSION(S): Gefapixant (45-mg twice daily) was not shown to be superior to placebo in reducing endometriosis-related pain, although the results directionally favored gefapixant. This trial result should be considered inconclusive given possible issues with treatment compliance. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03654326.

Oncology Combination Drug Development Strategies for Project Optimus.

The Project Optimus initiative from the FDA introduced a new dose optimization and selection paradigm in oncology drug development. The FDA has outlined approaches to dose optimization for single agents, but multiple oncology drugs are being developed for use in combination with other therapies. Dose optimization in the context of combination drug development is complex and requires a case-by-case approach. It necessitates commitment to the totality of available evidence, leveraging all relevant data on mechanism of action, nonclinical and clinical pharmacology, safety, and principles of model-informed drug development. In this article, we outline key considerations for sponsors and investigators pursuing dose optimization with combinatorial regimens. We illustrate important strategies for dose optimization in the combination setting using a range of hypothetical case examples that represent typical drug development scenarios. Close discussions and collaboration with regulators regarding the optimal approaches to these scenarios will continue to be critical.

Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.

Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a highly prevalent disorder with serious health consequences but limited therapeutic options. For a subset of those with OSA, a key underlying mechanism is hypersensitive chemoreflex control of breathing. There is no approved therapy that targets this endotypic trait. Here we determine whether the P2X3 receptor antagonist gefapixant, which is predicted to attenuate hypersensitive carotid chemoreflexes, reduces OSA severity in patients with chemoreflex-dependent OSA. METHODS: In a randomized placebo-controlled cross-over study, 24 patients with moderate-to-severe OSA (aged 39-68 years, non-CPAP users) whose disorder was partially responsive to supplemental oxygen (chemoreflex-dependent OSA) were treated with gefapixant 180 mg (or placebo) administered as tablets taken orally before bedtime for 7 days and assessed via overnight polysomnography. The primary analysis examined whether gefapixant treatment resulted in a greater reduction in the apnea-hypopnea index (AHI) from baseline than placebo. RESULTS: Gefapixant did not lower the AHI significantly more than placebo; the estimated ratio of the AHI on gefapixant versus placebo was 0.92 [90% CI: 0.73, 1.17]. Notably, nocturnal hypoxemia was increased (ratio of total sleep time with SpO2 <90% on gefapixant versus placebo = 2.08 [90% CI: 1.53, 2.82]), consistent with reduced chemoreflex output. Commonly reported adverse events with gefapixant included ageusia, dysgeusia, oral hypoaesthesia, nausea, somnolence, and taste disorders. CONCLUSIONS: Gefapixant, while generally well tolerated, did not reduce OSA severity in patients with chemoreflex-dependent OSA. P2X3 receptor antagonism is unlikely to provide an avenue for therapeutic intervention in OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Safety and Tolerability of Gefapixant (MK-7264) in Participants With Obstructive Sleep Apnea (MK-7264-039); URL: https://clinicaltrials.gov/study/NCT03882801; Identifier: NCT03882801.

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

Population pharmacokinetic analysis of the P2X3-receptor antagonist gefapixant.

Gefapixant, a P2X3-receptor antagonist, demonstrated objective and subjective efficacy in individuals with refractory or unexplained chronic cough. We report a population pharmacokinetic (PopPK) analysis that characterizes gefapixant pharmacokinetics (PKs), quantifies between- and within-participant variability, and evaluates the impact of intrinsic and extrinsic factors on gefapixant exposure. The PopPK model was initially developed using PK data from six phase I studies. Stepwise covariate method was utilized to identify covariates impacting PK parameters; the model was re-estimated and covariate effects were re-assessed after integrating PK data from three phase II and III studies. Simulations were conducted to evaluate the magnitude of covariate effects on gefapixant exposure. Of 1677 participants included in this data set, 1618 had evaluable PK records. Age, body weight, and sex had statistically significant, but not clinically relevant, effects on exposure. Degree of renal impairment (RI) had statistically significant and clinically relevant effects on exposure; exposure was 17% to 89% higher in those with versus without RI. Simulation results indicated that gefapixant 45 mg administered once daily to patients with severe RI has similar exposure to gefapixant 45 mg administered twice daily to patients with normal renal function. There were no significant effects of proton pump inhibitors or food. Of evaluated intrinsic and extrinsic factors, only RI had a clinically relevant effect on gefapixant exposure. Patients with mild or moderate RI do not require dosage adjustments; however, for patients with severe RI who are not on dialysis, gefapixant 45 mg once daily is recommended.

Clinical Formulation Bridging of Gefapixant, a P2X3-Receptor Antagonist, for the Treatment of Chronic Cough.

Gefapixant is a P2X3-receptor antagonist being developed for treatment of refractory or unexplained chronic cough. Four phase 1 studies were conducted in healthy participants that bridged the early-phase gefapixant formulation (F01) to the phase 3 (F04A) and intended commercial (F04B) formulations. In addition, food and proton pump inhibitor (PPI) coadministration effects on gefapixant exposure were assessed. The gefapixant free base formulation (F01) was used in the initial early-phase clinical studies. Adding citric acid to the F01 formulation (to generate F02) enhanced drug solubilization, resulting in similar bioavailability and mitigating food and gastric pH effects. The subsequently developed gefapixant citrate salt formulation (F04) achieved exposures that were comparable to F02 in the fed state (90%CIs of geometric mean ratios for area under the plasma concentration-time curve from time 0 extrapolated to infinity and maximum observed concentration were within 0.80 and 1.25) and were not meaningfully affected by food or PPIs (90%CIs of geometric mean ratios for area under the plasma concentration-time curve from time 0 extrapolated to infinity and maximum observed concentration were within 0.80 and 1.25). Minor compositional changes were made to generate the F04A and F04B formulations. In vitro dissolution studies were used to bridge F04 to F04A, and clinical bioequivalence was then established between F04A and F04B. These data support use of the proposed commercial gefapixant formulation without significant food and PPI effects.

Characterization of the absorption, metabolism, excretion, and mass balance of gefapixant in humans.

Gefapixant (MK-7264) is a first-in-class, selective antagonist of the P2X3 purinergic receptor currently being investigated as a therapeutic agent for the treatment of refractory or unexplained chronic cough. In non-clinical studies, gefapixant was eliminated primarily by renal excretion of the parent drug. The objective of this study was to assess the disposition of gefapixant in humans. The absorption, metabolism, and excretion profiles of gefapixant were assessed after oral administration of a single dose of [14 C]gefapixant to six healthy adult males. Following a single-oral [14 C]gefapixant dose to healthy adult males, the mass balance was achieved, with 98.9% of the administered radioactivity recovered in urine and feces. Elimination of gefapixant occurred primarily via renal excretion of the intact drug (64%); metabolism was a minor pathway of elimination of gefapixant (12% and 2% recovered in urine and feces, respectively). Single-dose administration of [14 C]gefapixant 50 mg was generally well tolerated in healthy adult males. The fraction of the anticipated therapeutic oral dose of gefapixant absorbed is estimated to be at least 78%. Gefapixant is expected to be the major circulating drug-related material in plasma, and the majority of the dosed drug will be excreted unchanged in urine.

Assessment of Pharmacokinetic Interaction Between Gefapixant (MK-7264), a P2X3 Receptor Antagonist, and the OATP1B1 Drug Transporter Substrate Pitavastatin.

Gefapixant (MK-7264, AF-219), a first-in-class P2X3 antagonist, is being developed as oral treatment for refractory or unexplained chronic cough. Based on in vitro data, gefapixant exerts inhibitory activity on the organic anion transporter (OAT) P1B1 transporter. Therefore, a drug-drug interaction study evaluating the potential effects of gefapixant on the OATP1B1 drug transporter, using pitavastatin as a sensitive probe substrate, was conducted. An open-label, 2-period, fixed-sequence study in 20 healthy adults 18 to 55 years old was conducted. In period 1, a 1-mg oral dose of pitavastatin was administered to each participant. After a ≥4-day washout, in period 2 participants received a 45-mg oral dose of gefapixant twice daily on days 1 through 4. On day 2 of period 2, pitavastatin was coadministered with the morning dose of gefapixant. Pitavastatin exposures following single-dose administration with and without multiple doses of gefapixant were similar: geometric mean ratio (90% confidence interval) of pitavastatin area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) (pitavastatin + gefapixant/pitavastatin alone) was 0.97 (0.93-1.02). The ratio of pitavastatin lactone AUC0-∞ to pitavastatin AUC0-∞ was also comparable between treatments. Administration of gefapixant and pitavastatin was generally well tolerated, with no safety findings of concern. These results support that gefapixant has a low potential to inhibit the OATP1B1 transporter.

Effects of Renal Impairment on the Pharmacokinetics of Gefapixant, a P2X3 Receptor Antagonist.

Gefapixant, a P2X3 receptor antagonist, has demonstrated efficacy in patients with refractory or unexplained chronic cough. We investigated the effect of renal impairment (RI) on the pharmacokinetics (PK) of gefapixant 50 mg in an open-label, single-dose study enrolling participants with moderate (n = 6) or severe (n = 6) RI, end-stage renal disease (ESRD; n = 6) under hemodialysis (HD) and non-HD conditions, and healthy matched controls (n = 6). Serial plasma and urine samples for gefapixant concentrations were collected at selected time points over 72 and 48 hours after dosing, respectively. Linear regression analysis predicted a 1.87-, 2.79-, and 3.76-fold higher exposure (area under the plasma concentration-time curve) for participants with mild, moderate, and severe RI, respectively, than that for healthy matched control participants. Categorical analysis exhibited a 2.98-, 4.43-, and 4.74-fold higher exposure for participants with moderate RI, severe RI, and ESRD, respectively, than that for healthy matched control participants. Apparent oral clearance and renal clearance was lower in participants with various degrees of RI, by 66% to 90%, compared with healthy matched control participants, explaining the increased gefapixant exposure with increasing degrees of renal impairment. Gefapixant area under the plasma concentration-time curve and maximum plasma concentration decreased by ≈25% under HD conditions compared to non-HD conditions. Single-dose administration of gefapixant was generally well tolerated in this study. The data from this trial informed the enrollment of phase 3 clinical trials that evaluated the efficacy and safety of gefapixant in >2000 participants with refractory or unexplained chronic cough. Those efficacy and safety data, combined with analysis of population pharmacokinetics from across the entire development program, will be used to evaluate the magnitude of the renal impairment effect in the refractory or unexplained chronic cough population and to determine any dose adjustment recommendations.

Assessment of the Effect of Pyrimethamine, a Potent Inhibitor of Multidrug and Toxin Extrusion Protein 1/2K, on the Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist.

Gefapixant (MK-7264, AF-219) is a first-in-class P2X3 antagonist in development for refractory or unexplained chronic cough. Gefapixant is primarily cleared by renal excretion. To assess the importance of the multidrug and toxin extrusion protein 1 (MATE1) and MATE2K transporters in the elimination of gefapixant, a drug-drug interaction study was conducted evaluating the effect of coadministration of a single dose of pyrimethamine, a competitive inhibitor of MATE1 and MATE2K, on the single-dose pharmacokinetics of gefapixant in healthy participants. Safety and tolerability were also assessed. In this open-label, 2-period, fixed-sequence study, a 45-mg dose of gefapixant was administered to 12 participants in period 1. After a 7-day washout, a 50-mg dose of pyrimethamine was administered 3 hours before a 45-mg dose of gefapixant in period 2. Compared with the administration of gefapixant alone, concomitant dosing of gefapixant with pyrimethamine increased the total gefapixant plasma exposure (area under the plasma concentration-time curve from time 0 to infinity) by 24%, reduced gefapixant renal clearance by 30%, and increased gefapixant mean terminal half-life from 7.7 to 10.3 hours. The most frequently reported adverse events were dysgeusia, hypogeusia, and dry mouth; all adverse events were considered of mild intensity and resolved by the end of the study. These results support that MATE1 and/or MATE2K contribute to the renal clearance of gefapixant, but the effect of inhibition of these transporters on gefapixant pharmacokinetics is not considered clinically meaningful.

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.

Clinical application of volumetric absorptive microsampling to the gefapixant development program.

In this paper we show the application of the Tasso OnDemand™, a novel automated sample collection device, in conjunction with volumetric absorptive microsampling (VAMS) for the development of gefapixant, a P2X3 receptor antagonist currently under clinical development for the treatment of refractory and unexplained chronic cough and endometriosis-related pain. A LC-MS/MS bioanalytical method was developed and validated using VAMS to support this development program. This method was utilized in a drug-drug interaction study to establish a mathematical bridging relationship with data obtained from a validated plasma assay used to support the program. The VAMS bioanalytical method and the predictability of the mathematical relationship is reported and discussed here.

Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough.

BACKGROUND: We present study designs, dose selection and preliminary patient characteristics from two phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: COUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are randomised, placebo-controlled, double-blind, parallel-group trials in subjects with RCC or UCC (age ≥18 years; cough duration ≥1 year; Cough Severity Visual Analogue Scale score ≥40 mm). The primary efficacy study periods are 12 weeks (40-week extension; COUGH-1) and 24 weeks (28-week extension; COUGH-2). Interventions include placebo, gefapixant 15 mg and gefapixant 45 mg (1:1:1 ratio). The primary efficacy endpoints are average 24-h cough frequency at Week 12 (COUGH-1) and Week 24 (COUGH-2). Awake cough frequency, patient-reported outcomes and responder analyses are secondary endpoints. RESULTS: The doses of 45 mg (to provide maximal efficacy and acceptable tolerability) and 15 mg (to provide acceptable efficacy and improved tolerability) were selected based on phase 1 and 2 studies. In COUGH-1, 730 participants have been randomised and treated; 74% are female with mean age of 59 years (39% over 65 years), and mean baseline duration of cough of 11.5 years. In COUGH-2, 1314 participants have been randomised and treated; 75% are female with mean age of 58 years (33% over 65 years), and mean baseline duration of cough of 11.1 years. CONCLUSIONS: These global studies include participants with baseline characteristics consistent with previous RCC and UCC studies and will inform the efficacy and safety profile of gefapixant in the treatment of patients with RCC and UCC.

Population-Pharmacokinetic Modeling of Tildrakizumab (MK-3222), an Anti-Interleukin-23-p19 Monoclonal Antibody, in Healthy Volunteers and Subjects with Psoriasis.

BACKGROUND: Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody recently approved for the treatment of chronic plaque psoriasis. METHODS: This analysis characterizes the population pharmacokinetics of subcutaneous tildrakizumab and identifies covariates influencing exposure in 2098 healthy volunteers and subjects with psoriasis. Tested covariates included body weight, formulation type, sex, age, race, serum albumin, creatinine clearance, Japanese origin, prior treatment with a biologic agent, subject status (subjects with psoriasis vs. healthy volunteers), and ethnicity. RESULTS: The pharmacokinetics was described by a one-compartment model with first-order absorption and elimination kinetics, and inter-individual variability on clearance, volume of distribution, and absorption rate constant. The pharmacokinetics was characterized by low clearance and limited volume of distribution. In subjects with psoriasis, the geometric mean clearance (coefficient of variation) was 0.32 L/day (38%), volume of distribution was 10.8 L (24%), and absorption and elimination half-life were 1.5 days (18%) and 23.4 days (23%), respectively, with an absorption lag time of 1.2 h. For the 100-mg dose, steady-state area under the plasma concentration vs. time curve for one dosing interval and maximum plasma concentration were 305 µg*day/mL (41%) and 8.1 µg/mL (34%), respectively. Steady state was achieved by 16 weeks with the clinical regimen (dosing on week 0 and week 4 and every 12 weeks thereafter) with 1.1-fold accumulation in maximum plasma concentration. Healthy subjects had 31% higher bioavailability than subjects with psoriasis. Subjects with increased body weight had a lower area under the plasma concentration-time curve at steady state vs. those with lower body weight. The modeled exposures were contained within clinical comparability bounds for all covariates including body weight. CONCLUSIONS: The pharmacokinetics of tildrakizumab behaves like a typical monoclonal antibody without requiring dosage adjustment. TRIAL REGISTRATION: NCT01729754, NCT01225731, NCT01722331.

Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.

PURPOSE: Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study. PATIENTS AND METHODS: Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose. RESULTS: Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption. CONCLUSION: The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.

PK of immunoconjugate anticancer agent CMD-193 in rats: ligand-binding assay approach to determine in vivo immunoconjugate stability.

BACKGROUND: Antibody-drug conjugates (ADCs) are a new generation of anticancer therapeutics. The objective of this manuscript is to propose a methodology that can be used to assess the stability of the ADCs by using the PK data obtained by ligand-binding assays that measure various components of ADCs. RESULTS: The ligand-binding assays format of different components of ADCs provided unique valuable PK information. The mathematical manipulation of the bioanalytical data provided an insight into the in vivo integrity, indicating that the loading of the calicheamicin on the G193 antibody declines in an apparent slow first-order process. CONCLUSION: This report demonstrates the value of analyzing various components of the ADC and their PK profiles to better understand the disposition and in vivo stability of ADCs.

The effect of the neonatal Fc receptor on human IgG biodistribution in mice.

The neonatal Fc receptor (FcRn) plays a pivotal role in IgG homeostasis, i.e., it salvages IgG antibodies from lysosomal degradation following fluid-phase pinocytosis, thus preventing rapid systemic elimination of IgG. Recombinant therapeutic antibodies are typically composed of human or humanized sequences, and their biodistribution, or tissue distribution, is often studied in murine models, although, the effect of FcRn on tissue distribution of human IgG in rodents has not been investigated. In this report, an (125)I-labeled human IgG1 antibody was studied in both wild type C57BL/6 (WT) and FcRn knockout (KO) mice. Total radioactivity in both plasma and tissues (0-96hr post-dose) was measured by gamma-counting. Plasma exposure of human IgG1 were significantly lower in FcRn KO mice, which is consistent with the primary function of FcRn. Differences in biodistribution of human IgG to selected tissues were also observed. Among the tissue examined, the fat, skin and muscle showed a decrease in tissue-to-blood (T/B) exposure ratio of human IgG1 in FcRn KO mice comparing to the WT mice, while the liver, spleen, kidney, and lung showed an increase in the T/B exposure ratio in FcRn KO mice. A time-dependent change in the T/B ratios of human IgG1 was also observed for many tissues in FcRn KO mice. These results suggest that, in addition to its role in IgG elimination, FcRn may also play a role in antibody biodistribution.