Danuglipron (PF‐06882961) is an oral, small‐molecule glucagon‐like peptide‐1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is ...prevalent in patients with T2D. This Phase 1, open‐label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate eGFR unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60‐89 mL/min), moderate (eGFR 30‐59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log‐linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20‐mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function.
Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the ...basal ganglia.
This study with PDE10A radioligand 18FMNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function for the quantification of 18FMNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, 18FMNI-659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassen's plot. Serum concentrations of PF-02545920 were measured to determine the relationship between concentration and occupancy.
Based on Method 1, striatal PDE10A occupancy increased with increasing PF-02545920 dose: 14–27% at 10 mg dose (N = 4) and 45–63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassen's plot Method 2: 10 mg: 14–37%; 20 mg: 46–55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL.
Single oral doses of 10 mg or 20 mg of PF-02545920 were safe and well tolerated in healthy male volunteers NCT# 01918202.
•Single oral doses (10 mg, 20 mg) of PF-02545920 were safe and well tolerated in healthy male volunteers.•Enzyme occupancy of PF-02545920 obtained using 18FMNI-659 PET was in the expected range.•Striatal PDE10A occupancy increased with increasing PF-02545920 dose and exposure, reaching ∼50% following the 20 mg single dose.•A 20 mg oral dose of PF-02545920 provides sufficient target brain occupancy for evaluation in future PDE10 clinical trials.
Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic bone marrow transplantation. In steroid-refractory aGVHD, mortality is very high. Pentostatin, a potent inhibitor of ...adenosine deaminase, induces lymphocyte apoptosis and may be useful in the treatment of this condition.
We have conducted a phase I dose escalation study of pentostatin in patients with steroid-refractory aGVHD. Twenty-three patients were enrolled. Starting dose was 1 mg/m2/d by intravenous injection for 3 days.
The maximum tolerated dose was found to be 1.5 mg/m2/d. Late infections at the 2-mg/m2/d dose level were believed to be dose limiting toxicities. Lymphopenia was universal, but the neutrophil count was generally not affected. Fevers associated with neutropenia were not observed. Otherwise, the drug was well tolerated, with only modest elevations of liver function tests and thrombocytopenia, each being observed in a single patient. Twenty-two patients were assessable for response, including 14 complete responses (63%) and three partial responses (13%). Median survival after therapy for the group was 85 days (range, 5 to 1,258 days).
The suggested intravenous dose for a phase II study will be 1.5 mg/m2/d for 3 days. Pentostatin has activity in patients with steroid-refractory aGVHD that is worth exploring in future trials.
Multiple-dose pharmacokinetics (PK) and safety were investigated in this phase 1 study of PF-06372865, a positive allosteric modulator of α2/3/5 subunit-containing γ-aminobutyric acid A receptors ...(NCT03351751). In 2 cohorts (7-8 PF-06372865 and 2 placebo in each cohort), healthy adult subjects received twice-daily oral doses of PF-06372865 for 21 days, which included titration in the first 7 days, followed by a maintenance dose of 25 mg twice daily (Cohort 1) and 42.5 mg twice daily (Cohort 2) for 14 days. Serial PK samples were collected on days 1 and 21. Nineteen subjects were assigned to study treatments; 18 completed the study. Approximate dose-proportional increases in maximum plasma concentratin and area under the plasma concentration-time curve over the dosing interval were observed. PF-06372865 was rapidly absorbed with a median time to maximum concentration of 1 to 2 hours following both single- and multiple-dose administration. Mean terminal elimination half-life on day 21 was approximately 11 hours in both cohorts. All adverse events were mild; the most frequently reported was dizziness. After titration, there were no reports of somnolence. There were no clinically significant safety findings, including a lack of withdrawal symptoms on discontinuation of treatment. These results demonstrate that PF-06372865 is safe and well tolerated at doses estimated to achieve high receptor occupancy (>80%), a profile differentiated from nonselective benzodiazepines.
OBJECTIVEThe objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at ...α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy.
METHODSSeven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.5 mg PF-06372865, 2 mg lorazepam (active control), and placebo. Standardized photosensitivity ranges (SPRs) to IPS were recorded at screening, predose, and 1, 2, 4, and 6 hours postdose. The primary endpoint was the average least squares mean change in the SPR in the participantʼs most sensitive eye condition, across all time points.
RESULTSBoth doses of PF-06372865 produced a marked and statistically significant mean reduction in SPR compared to placebo, which was similar in degree to lorazepam. There was complete suppression of SPR in 6/7 participants following PF-06372865 or lorazepam administration. PF-06372865 was safe and well-tolerated.
CONCLUSIONPF-06372865 demonstrated highly robust efficacy. This demonstrates anticonvulsant activity of a novel α2/3/5-subtype selective GABAA PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted.
CLINICALTRIALS.GOV IDENTIFIERNCT02564029.
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.
Multiple‐dose pharmacokinetics (PK) and safety were investigated in this phase 1 study of PF‐06372865, a positive allosteric modulator of α2/3/5 subunit‐containing γ‐aminobutyric acid A receptors ...(NCT03351751). In 2 cohorts (7‐8 PF‐06372865 and 2 placebo in each cohort), healthy adult subjects received twice‐daily oral doses of PF‐06372865 for 21 days, which included titration in the first 7 days, followed by a maintenance dose of 25 mg twice daily (Cohort 1) and 42.5 mg twice daily (Cohort 2) for 14 days. Serial PK samples were collected on days 1 and 21. Nineteen subjects were assigned to study treatments; 18 completed the study. Approximate dose‐proportional increases in maximum plasma concentratin and area under the plasma concentration–time curve over the dosing interval were observed. PF‐06372865 was rapidly absorbed with a median time to maximum concentration of 1 to 2 hours following both single‐ and multiple‐dose administration. Mean terminal elimination half‐life on day 21 was approximately 11 hours in both cohorts. All adverse events were mild; the most frequently reported was dizziness. After titration, there were no reports of somnolence. There were no clinically significant safety findings, including a lack of withdrawal symptoms on discontinuation of treatment. These results demonstrate that PF‐06372865 is safe and well tolerated at doses estimated to achieve high receptor occupancy (>80%), a profile differentiated from nonselective benzodiazepines.
Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a ...mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study.
The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points.
Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed.
Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.
The purpose of this study was to determine if the 10-50 microM plasma concentrations of suramin required to produce chemosensitization could be achieved by oral administration.
Rats were given an ...oral dose of 100, 300, or 500 mg/kg unlabeled suramin by oral gavage. Rats receiving the 300 mg/kg oral dose of suramin also received a concomitant intravenous bolus injection of 50 microCi/kg of 3Hsuramin, administered 57 min after the oral dose. The intravenous data were used to calculate the clearance. Serial plasma samples were collected over 24-336 h. Plasma concentration-time profiles were analyzed using noncompartmental and compartmental methods. The pharmacokinetic parameters derived for the 300 mg/kg oral and 50 microCi/kg intravenous doses were used to calculate the bioavailability and AUC at the three oral dose levels.
Plasma concentrations declined biexponentially following intravenous administration, with a distribution half-life of approximately 2 h and an estimated terminal half-life of 276 h. Suramin absorption following oral gavage was variable and incomplete with mean maximal plasma concentrations of 9.04, 72.6, and 64.4 microg/ml at doses of 100, 300, and 500 mg/kg, respectively. Seven of 15 rats exhibited two peak plasma concentrations at approximately 1 h and 3 to 12 h, suggesting the existence of multiple absorption sites and/or enterohepatic circulation. Oral bioavailability, calculated using the clearance of the intravenous tracer dose, was <3% at all three dose levels.
While plasma concentrations resulting from the 300 and 500 mg/kg oral doses of suramin were in the concentration range required to produce chemosensitization, the low bioavailability limits the usefulness of oral administration.
We recently reported strong bactericidal activity of the oxazolidinone PNU-100480 and its ability to increase the initial bactericidal effect of various combinations of first-line tuberculosis drugs ...and moxifloxacin in a murine model.
To investigate whether the addition of PNU-100480 to the standard first-line regimen of rifampin, isoniazid, and pyrazinamide could shorten the duration of treatment necessary to prevent relapse after treatment discontinuation.
Following aerosol infection with Mycobacterium tuberculosis H37Rv and a 13-day incubation period, control mice were treated with the first-line regimen while test mice received the same regimen with PNU-100480 or linezolid added for the first 2 or 4 months. Efficacy was assessed on the basis of quantitative cultures of lung homogenates performed monthly during treatment and 3 months after completion of 3, 4, 5, or 6 months of treatment to determine the relapse rate.
After 2 months of treatment, mice receiving PNU-100480 in addition to the first-line regimen had lung CFU counts two orders of magnitude lower than control mice receiving the first-line regimen alone. Relapse rates after 4 months of treatment were 90, 35, and 5% when PNU-100480 was added to the first-line regimen for 0, 2, and 4 months, respectively. When the total treatment duration was 3 months, relapse rates were 85 and 35 to 45% when mice received PNU-100480 for 2 and 3 months, respectively; all control mice remained culture positive at the time of treatment completion with 17 to 72 CFU per lung. Addition of linezolid to the first-line regimen had an antagonistic effect resulting in higher CFU counts and failure to render mice culture-negative in 4 months of treatment.
Together with previous findings, these results confirm that PNU-100480, which is now in Phase I clinical testing, has sterilizing activity in the murine model and suggest that it may be capable of shortening treatment duration for drug-susceptible as well as drug-resistant tuberculosis in humans.
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