This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse events were deemed not drug related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PK/PD model well described the tendency of observed CSF Aβ data and the steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials.Dementia is a progressive, neurodegenerative disorder affecting ~ 50 million people worldwide, 1 of which Alzheimer's disease (AD) is most common. 1 Treatments including cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists help with AD symptoms. 2 However, a medical need exists for agents capable of modifying and slowing AD progression. AD pathology in the brain is characterized by senile, amyloid plaques comprising a core of amyloid-β (Aβ) peptide fibrils, 3,4 and neurofibrillary tangles of primarily hyperphosphorylated tau protein. 4,5 Amyloid precursor protein (APP) is a transmembrane protein that is cleaved during processing by γ-secretase to generate Aβ peptides of various lengths, including Aβ37,38,40, and 42. 6,7 Aβ42 has a higher aggregation

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

dThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (C max ), the concentration at end of dosing interval (C ), and the area under the curve over dosing interval (AUC ). Safety and tolerability were also assessed. MVC geometric mean AUC , C max , and C were increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUC , C max , and C decreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected. M araviroc (MVC) is a first-in-class selective chemokine coreceptor type-5 (CCR5) antagonist indicated for the treatment of CCR5-tropic (R5) HIV-1 infection in both treatmentnaive and treatment-experienced patients in the United States (1), as well as treatment-experienced patients in the European Union (2). MVC is primarily metabolized by hepatic and intestinal cytochrome P450 3A4 (CYP3A4) enzymes, with negligible metabolic activity for other CYP enzymes, and is also a substrate for the efflux transport P-glycoprotein (P-gp) (3).As a component of combination regimens, MVC is frequently administered with other antiretroviral agents, including protease inhibitors (PIs) (4, 5). Since the majority of PIs are inhibitors of CYP3A and P-gp, potential exists for drug interactions with MVC. Indeed, MVC exposures have been shown to be increased in the presence of atazanavir, ritonavir (RTV)-boosted atazanavir (atazanavir/r), saquinavir, saquinavir/r, daru...

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double‐blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2‐sided 90% confidence intervals (CIs) for all time‐matched least‐squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure–response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model‐derived baseline and placebo‐adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5‐8.2 milliseconds) and 13.7 milliseconds (12.0‐15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20‐millisecond threshold of clinical concern in oncology.