A Phase 1 first-in-human study of the safety, tolerability, and pharmacokinetics of the ROBO2 fusion protein PF-06730512 in healthy participants.

Proteinuria associated with podocyte effacement is a hallmark of focal segmental glomerulosclerosis (FSGS). Preclinical studies implicated ROBO2/SLIT2 signaling in the regulation of podocyte adhesion, and inhibition of this pathway is a novel target to slow FSGS disease progression. This first-in-human dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of PF-06730512, an Fc fusion protein that targets the ROBO2/SLIT2 pathway, in healthy adults. In this Phase 1, double-blind, sponsor-open study, single ascending dose (SAD) cohorts were randomized to receive up to 1000 mg or placebo intravenously (IV); multiple ascending dose (MAD) cohorts were randomized to receive up to 400 mg subcutaneous (SC) doses, 1000 mg IV dose, or matching placebo. Safety evaluations were performed up to 71 (SAD) and 113 (MAD) days after dosing; blood samples were collected to measure serum PF-06730512 concentrations and antidrug antibodies (ADA) to PF-06730512. Seventy-nine participants (SAD, 47; MAD, 32) were enrolled. There were 108 mild (SAD, 46; MAD, 62) and 21 moderate (SAD, 13; MAD, 8) treatment-emergent adverse events (TEAEs); no deaths, treatment-related serious AEs, severe TEAEs, or infusion reactions were reported. PF-06730512 exposure generally increased in an approximately dose-proportional manner; mean t1/2 ranged from 12-15 days across 50-1000 mg doses. Immunogenicity incidence was low (SAD, 0 ADA+; MAD, 2 ADA+). In conclusion, single IV doses of PF-06730512 up to 1000 mg and multiple IV and SC dosing up to 1000 and 400 mg, respectively, were safe and well tolerated in healthy participants. Further trials in patients with FSGS are warranted. Clinical trial registration: Clinicaltrials.gov: NCT03146065.

A mechanistic pharmacokinetic model with drug and antidrug antibody interplay, and its application for assessing the impact of immunogenicity response on bioequivalence testing.

AIMS: Single-dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice for bioequivalence determination for decades. This preference has been recently extended to PK similarity studies of proposed biosimilars. However, PK similarity studies can be complicated by the effect of immunogenicity response on drug disposition. The impact is exacerbated when there is an imbalance in host-specific immunological characteristics of subjects between the test and reference groups. Such complications remain poorly understood. The purpose of this communication is to show that the impact of immunogenicity response on PK similarity determination can be critical, using adalimumab as an example. METHODS: Data for adalimumab concentrations and immunogenicity response over 10 weeks were obtained from 133 healthy subjects receiving a 40 mg dose of Humira® in a PK similarity study. Also, a population PK model with a mechanistic construct for delineating the interplay between adalimumab disposition and antidrug antibodies response was utilized to estimate via simulation the probability that a PK similarity study would fail in typical study settings. RESULTS: The simulations showed that the immunogenicity response can have a profound impact on the outcome of PK similarity determination. As such, the probability of failing to achieve the similarity conclusion increased to 51.9%, from 13.8% in the absence of immunogenicity response. CONCLUSION: This study provides a model-based framework for better understanding of how a PK similarity study can be optimally designed and for interpretation of the outcome of PK similarity determination when the drug disposition is affected in the presence of immunogenicity response.

Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-ß Peptides in Randomized Phase I Studies.

γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-ß (Aß) 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 Aß 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 eventswere deemed not drug related. PF-06648671 decreased Aß42 and Aß40 concentrations in CSF, with greater effects on Aß42, and increased Aß37 and Aß38 levels, particularly Aß37. No significant change in total Aß was observed. The PK/PD model well described the tendency of observed CSF Aß data and the steady-state effects of PF-06648671, supporting its use for predicting central Aß effects and optimal dose selection for GSMs in future trials.

Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects.

Crizotinib (Xalkori®) is an orally administered, selective, small-molecule, ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition factor/hepatocyte growth factor receptor tyrosine kinases, and has recently been approved for the treatment of ALK-positive non-small cell lung cancer. The absolute bioavailability of crizotinib, effect of a high-fat meal on crizotinib pharmacokinetics (PK), and bioequivalence of several oral formulations (powder in capsule [PIC], immediate-release tablet [IRT], and commercial formulated capsule [FC]) were evaluated in two phase I clinical studies involving healthy volunteers who received single doses of crizotinib. PK parameters for crizotinib and its metabolite, PF-06260182, were determined using non-compartmental methods. The absolute oral bioavailability of crizotinib was approximately 43%, with a slight decrease in crizotinib exposures (area under the plasma concentration-time profile and maximum plasma concentration) following a high-fat meal that was not considered clinically meaningful. The FC was bioequivalent to the clinical development IRT and PIC formulations. No serious adverse events were observed during either study and the majority of adverse events were mild, the most common being diarrhea. Single-dose crizotinib could be safely administered to healthy subjects.

The effects of boceprevir and telaprevir on the pharmacokinetics of maraviroc: an open-label, fixed-sequence study in healthy volunteers.

OBJECTIVE: To evaluate the effects of boceprevir (BOC) and telaprevir (TVR) on the pharmacokinetics (PK) of maraviroc (MVC) in healthy volunteers. METHODS: In this open-label, fixed-sequence study, 14 volunteers received MVC 150 mg twice daily alone for 5 days (period 1), followed by MVC + BOC 800 mg 3 times daily and MVC + TVR 750 mg 3 times daily, each for 10 days in periods 2 and 3, respectively, with a ≥10-day wash-out. PK was analyzed on day 5 of period 1 and day 10 of periods 2 and 3. Safety was also assessed. RESULTS: Ratios of the adjusted geometric means (90% confidence intervals) for MVC area under the curve from predose to 12 hours, maximum plasma concentration, and plasma concentration at 12 hours were 3.02 (2.53 to 3.59), 3.33 (2.54 to 4.36), and 2.78 (2.40 to 3.23), respectively, for MVC + BOC versus MVC alone, and 9.49 (7.94 to 11.34), 7.81 (5.92 to 10.32), and 10.17 (8.73 to 11.85), respectively, for MVC + TVR versus MVC alone. PK profiles for MVC + BOC or TVR were consistent with historic values for BOC and TVR monotherapy. Adverse event incidence was higher with MVC + BOC and MVC + TVR versus MVC alone. Dysgeusia (50%) and pruritus (29%) occurred most commonly with MVC + BOC, and fatigue (46%) and headache (31%) with MVC + TVR. There were no serious adverse events. CONCLUSIONS: MVC exposures were significantly increased with BOC or TVR, therefore MVC should be dosed at 150 mg twice daily when coadministered with these newly approved hepatitis C protease inhibitors. No dose adjustment for BOC or TVR is warranted with MVC. MVC + BOC or TVR was generally well tolerated with no unexpected safety findings.

Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients.

UNLABELLED: More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from -0.97 log(10) IU/mL with filibuvir given at 100 mg twice daily to -2.30 log(10) IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log(10) IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing. CONCLUSION: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients.