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Objective: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). Methods: In this open-label, randomized, 2-part, 2-period cross over study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). Results: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/SIMVA and EZE + SIMVA were generally well tolerated. Conclusions: The low est and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dos ages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tab let across the clinical dose range. [ABSTRACT FROM AUTHOR]

Background/aims: MK-0431 (sitagliptin) is a selective DPP-IV inhibitor in Phase III development for the treatment of type 2 diabetes. Since sitagliptin is expected to be commonly co-administered with statins, the effect of sitagliptin on the pharmacokinetics (PK) of simvastatin, a CYP3A4 substrate, was evaluated.Methods: Twelve healthy subjects were randomized to 2 treatment periods: (A) a single oral dose of simvastatin 20 mg and (B) daily oral doses of 200 mg sitagliptin on Days 1 through 5 and a single oral dose of simvastatin 20 mg on Day 5. Plasma was collected for 24 hours following each simvasatin dose to determine the PK of active HMG-CoA reductase inhibitors (represents all active inhibitors in plasma; primary analyte), total HMG-CoA reductase inhibitors, simvastatin, and simvastatin acid.Results: Active inhibitor geometric mean ratio (simvastatin+sitagliptin/simvastatin) and the 90% CI for AUC0-last and Cmax were 1.06 (0.88, 1.26) and 0.94 (0.66, 1.34), respectively, with no meaningful difference in Tmax between treatments (median 1.8 hours for both treatments). Additionally, there were no clinically or statistically meaningful differences in AUC0-last, Cmax or Tmax between treatments for the other three analytes evaluated (total inhibitors, simvastatin and simvastatin acid). Sitagliptin and simvastatin were well tolerated.Conclusions: Multiple oral doses of sitagliptin do not meaningfully alter the pharmacokinetics of simvastatin.Clinical Pharmacology & Therapeutics (2005) 79, P48–P48; doi: 10.1016/j.clpt.2005.12.171 [ABSTRACT FROM AUTHOR]

Cholesteryl ester transfer protein (CETP) inhibitor is a target for both lowering low-density lipoproteins and raising high-density lipoproteins. Anacetrapib was the lead compound in our cholesteryl ester transfer protein inhibitor program. Preclinical studies were initiated to support the safety of anacetrapib deposition in adipose tissue, followed by a clinical trial to evaluate the effects of anacetrapib in people with vascular disease. An ultra-high performance liquid chromatography/tandem mass spectrometry method was developed to determine tissue anacetrapib concentrations in the adipose of three animal species and humans. The assays were validated in the concentration ranges of 5-5000 ng/ml and 0.1-100 μg/ml. The anacetrapib concentrations in adipose tissue from preclinical and clinical studies were determined.

Background: Clesrovimab (MK-1654) is an investigational, half-life extended human monoclonal antibody (mAb) against RSV F glycoprotein in clinical trials as a prophylactic agent against RSV infection for infants., Methods: This adult study measured clesrovimab concentrations in the serum and nasal epithelial lining fluid (ELF) to establish the partitioning of the antibody after dosing. Clesrovimab concentrations in the nasal ELF were normalized for sampling dilution using urea concentrations from ELF and serum. Furthermore, in vitro RSV neutralization of human nasal ELF following dosing was also measured to examine the activity of clesrovimab in the nasal compartment., Findings: mAbs with YTE mutations are reported in literature to partition ∼1-2 % of serum antibodies into nasal mucosa. Nasal: serum ratios of 1:69-1:30 were observed for clesrovimab in two separate adult human trials after urea normalization, translating to 1.4-3.3 % of serum concentrations. The nasal PK and estimates of peripheral volume of distribution correlated with higher extravascular distribution of clesrovimab. These higher concentration of the antibody in the nasal ELF corroborated with the nasal sample's ability to neutralize RSV ex vivo. An overall trend of decreased viral plaque AUC was also noted with increasing availability of clesrovimab in the nasal ELF from a human RSV challenge study., Interpretation: Along with its extended half-life, the higher penetration of clesrovimab into the nasal epithelial lining fluid and the associated local increase in RSV neutralization activity could offer infants better protection against RSV infection., Competing Interests: Declaration of Competing Interest JYP, BMM, AT, YZ, LC, RAR, MDS, YC, HL, BR, AOA, KAV are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (or were at the time of the study), and may hold stock in Merck & Co., Inc. Rahway, NJ, USA. AP, nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Historically, a neutralization antibody (NAb) assay is considered critical in immunogenicity assessment of biologic therapeutics, even with low anti-drug antibody (ADA) positive rates. In 2019, FDA new guidelines issued on immunogenicity testing acknowledged the possibility of using "a highly sensitive PD marker or an appropriately designed PK assay or both that generate data that inform clinical activity" to replace a NAb assay. In the current manuscript, we present data for PK, PD, and ADA assays which collectively succeed to replace the standalone NAb assay. The data include a total LC/MS-based PK assay, a serum neutralization antibody (SNA) assay that essentially measures pharmacodynamically functional PK and can detect NAb activity in the presence of 1:1 ratio of drug, and a highly drug-tolerant ADA assay. In addition, a model-based meta-analysis (MBMA) demonstrated that the ability of SNA assay to detect NAb at 1:1 ratio of drug is sensitive enough to monitor clinically meaningful efficacy change, which is 50% reduction of SNA titer. Our strategy of preparing a holistic data package discussed here may provide a roadmap to the community for alternatives in assaying neutralizing activity of ADA., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability. High-resolution mass spectrometry evaluations of stressed and aged verubecestat DBS samples revealed the presence of two hydrolysis degradants. To minimize instability, new DBS handling procedures were implemented that provided additional desiccant and minimized the time to analysis. Both verubecestat hydrolysis products were previously discovered and synthesized during active pharmaceutical ingredient stability characterization. A liquid chromatography-mass spectrometry assay to quantitate the dominant verubecestat degradant in DBS samples was developed and validated. The application of this method to stressed and aged verubecestat DBS samples confirmed that degradant concentrations accounted for the observed decreases in the verubecestat concentration. Furthermore, after increasing desiccant amounts, degradant concentrations accounted for approximately 7% of the verubecestat concentration in DBS clinical samples, indicating that issues with sample handling were minimized with new storage and shipping conditions. This case study illustrates the challenges with employing new sampling techniques in large, global trials, and the importance of anticipating and mitigating implementation risks., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary., Methods: Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population., Findings: The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants., Interpretation: An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens., Competing Interests: Declaration of Competing Interest BM, RR, LC, JC, WL, YZ, QH, WG, DS, BR, AE, SS, EL, AA and KV are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (or were at the time of the study), and may hold stock in Merck & Co., Inc., Kenilworth, NJ, USA. JRS is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may hold stock in Merck & Co., Inc., Kenilworth, NJ, USA and reports other investments that are less than 1% ownership for any company. JL, NP, LQ, HW, ES, BG, and FB are employed by Certara, Princeton, NJ, USA (or were employed at the time of the study) and may hold shares in Certara, Princeton, NJ, USA. Certara received funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, for modelling work. ASYC is employed by Certara, Princeton, NJ, USA and holds stock in Certara, Princeton, NJ, USA and AstraZeneca, Cambridge, UK and is a chair of IQ consortium TALG and CLPG Pediatric PBPK group. JM, MK, AP, and JFK : nothing to disclose., (Copyright © 2021 Merck Sharp & Dohme Corp., The Author(s). Published by Elsevier B.V. All rights reserved.)

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.

Aim: A method to quantitate doravirine (MK-1439) in human plasma has been developed to support human clinical trials designed to evaluate the safety, pharmacokinetics and efficacy of the compound. Methodology & results: The analyte was extracted using liquid-liquid extraction, separated on a reverse phase HPLC column, and detected on an API-4000 mass spectrometer using a Turbo-Ion spray source in positive ionization mode coupled with multiple reaction monitoring mode was used for quantification. The dynamic range for the assay was 0.02-10 ng/ml using 100 μl of human plasma. Conclusion: The assay was found to be sensitive, selective and reproducible and applied to support the doravirine clinical development program.

In vitro cadaver skin permeation studies are often conducted to characterize the permeation profile of compounds for dermal delivery. However, its utility could be limited in the case of topical products because of lack of reliable prediction of in vivo skin kinetics. In this paper, the use of in vivo skin biopsy data to guide topical formulation development is described. A formulation was developed by compounding MK-0873, a phosphodiesterase 4 (PDE4) inhibitor, into a commercially available cream base. The cream was characterized by skin pharmacokinetic studies in minipigs, which demonstrated that MK-0873 concentrations in the epidermis and dermis were substantially higher than the IC80 for human whole blood PDE4 inhibition of ∼200 nM, suggesting that cream should provide sufficient skin exposure to assess clinical efficacy. In toxicological studies, after 1 month repeat application in minipigs minor dermal irritation and minimal systemic exposure were observed. Based on these preclinical data, the cream formulation was chosen for single rising dose clinical studies, where plasma levels of MK-0873 were mostly below the LOQ, whereas skin biopsy concentrations ranged from 6.5 to 25.1 μM. These data suggested that minipig skin biopsy model can be a valuable tool to assess performance of topical formulations and guide formulation development., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Two randomized, two-period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG-CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once-daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once-daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once-daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by approximately 30% for Cmax and approximately 40% for AUC), but time to reach Cmax (tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (approximately 25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG-CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug-metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.

A sensitive and reliable procedure for the simultaneous determination of simvastatin (SV) and its active beta-hydroxy acid metabolite (SVA) in human plasma was developed and validated. The analytes were extracted simultaneously from 0.5 ml aliquots of human plasma samples by methyl tert-butyl ether (MTBE) via Chem Elut cartridge extraction [also called liquid-solid extraction (LSE) or liquid-liquid cartridge extraction (LLCE)], separated through a Kromasil C(18) column (50 x 2 mm i.d. 5 microm) and detected by tandem mass spectrometry with a turbo ionspray interface. Stable isotope-labeled SV and SVA, (13)CD(3)-SV and (13)CD(3)-SVA, were used as internal standards. SV and SVA were detected in positive and negative ion modes, respectively, via within-run polarity switching. The use of Chem Elut cartridges not only provided a simple and efficient means of plasma sample extraction but also successfully reduced the interconversion between SV and SVA to an undetectable (for lactonization of SVA) or negligible (<0.07%, for hydrolysis of SV) level. The method showed excellent reproducibility, with intra- and inter-assay precisions <4.5% (RSD), and intra- and inter-assay accuracy between 94% and 107% of nominal values, for both analytes. The extraction recoveries were 78% and 87% on average for SV and SVA, respectively. The analyte was found to be stable in plasma through three freeze (-70 degrees C)-thaw (4 degrees C) cycles and for at least 3 h under bench-top storage condition in an ice-bath (4 degrees C), and also in the reconstitution solution at 4 degrees C for at least 24 h. The method has a lower limit of quantitation (LOQ) of 50 pg ml(-1) with a linear calibration range of 0.05-50 ng ml(-1) for both analytes, and has proved to be very reliable for the analysis of clinical samples., (Copyright 2000 John Wiley & Sons, Ltd.)