Abstract Background: Talazoparib (TAL), an oral poly ADP-ribose polymerase inhibitor, is under investigation in multiple oncologic clinical trials and has been submitted to the US FDA for use in patients (pts) with germline BRCA-mutated, HER2-negative advanced breast cancer. International Conference on Harmonisation guidance recommends all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in pts is required in the registration dossier. The effect of steady-state (ss) TAL (1 mg once daily) on cardiac repolarization in pts with advanced solid tumors was evaluated in an open-label phase 1 study (NCT03042910). Methods: Continuous 12-lead electrocardiogram (ECG) recordings were collected at baseline (Day -1); time-matched pharmacokinetic (PK) samples and continuous ECG recordings were obtained on Days 1, 2, and 22 (when TAL concentrations achieved ss). On Day -1, pts had continuous 12-lead ECG recording starting at Time 0 (Day 1 dosing time) for 6 hrs. On Days 1 and 22, ECG recording started 45 min before TAL administration and continued for 6 hrs post dose and blood samples for PK were collected before dose and at 1, 2, 4, and 6 hrs post dose. On Day 2, a 30-min ECG recording and a PK sample were obtained before dose at Time 0. Continuous ECG recordings were submitted to a central laboratory; triplicate 10-sec ECGs were extracted from a 5-min extraction window beginning 15 min before each PK collection time. ECG measurements were reported via blinded manual adjudication process and included PR interval, QT interval, RR interval, and QRS complex. The QT interval was corrected for effect of heart rate using Fridericia's correction (QTcF) and Bazett's correction (QTcB). The estimate of change from time-matched baseline and its 2-sided 90% confidence interval (CI) was calculated for each nominal time point using PROC MEANS. Additionally, a prespecified PK/pharmacodynamic (PD) model was used to describe the relationship between plasma TAL concentrations ([TAL]) and QTc. The prespecified linear mixed-effects model included [TAL], time (categorical), and treatment with random pt effects on [TAL] and the intercept. If the upper bounds (UB) of 1-sided 95% CIs of time-matched ΔQTc for all ECG time points were <20 msec and the UB of 1-sided 95% CIs of the predicted ΔQTc at the mean ss maximum [TAL] was <20 msec, the effect of TAL on QTc was not of clinical relevance. Results: 37 of 38 pts enrolled received TAL and were included in the ECG and PK/PD analyses. No pts had a postbaseline absolute maximum QTcF or QTcB ≥500 msec or ΔQTc ≥60 msec. The UB of the 1-sided 95% CI for the time-matched ΔQTcF and ΔQTcB were <12 msec at all nominal ECG time points. In the PK/PD analysis, the slopes (95% CI) of QTcF-[TAL] and QTcB-[TAL] relationships were -0.14 (-0.78 to 0.50) msec/ng/mL and -0.24 (-0.88 to 0.41) msec/ng/mL, respectively, indicating that TAL did not have a concentration-dependent effect on QTcF or QTcB. Conclusion: TAL does not have a clinically relevant effect on QTc. Funding: Medivation LLC, acquired by Pfizer. Citation Format: Hoffman J, Chakrabarti J, Wainberg ZA, Plotka A, Babu S, Milillo Naraine A, Kanamori D, Moroose R, Nguyen L, Wang D. Evaluation of the effects of talazoparib on QT interval prolongation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-07.

Background: Racial and ethnic variations in CYP enzyme polymorphisms have been associated with population differences in drug metabolism. This study evaluated the pharmacokinetics of single- and multiple-dose desvenlafaxine in healthy Korean subjects. Methods: This randomized, double-blind, placebo-controlled, study enrolled 38 healthy Korean adults (aged 18 to 55 years). Subjects received single oral doses of placebo or desvenlafaxine (administered as desvenlafaxine succinate) 50, 100, or 200 mg on day 1, followed by 5 days of once daily dosing on days 4 to 8. Blood samples were collected pre-dose and over 72 h post-dose on days 1 and 8. Plasma desvenlafaxine concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry and pharmacokinetic parameters were calculated using non-compartmental method. Tolerability was assessed through adverse event reporting. Results: For both single-and multiple-dose desvenlafaxine, peak plasma concentration and area under the concentration-time curve increased approximately linearly with dose. For the 4-fold increase in dose from 50 mg to 200 mg desvenlafaxine, area under the concentration-time curve from time 0 extrapolated to infinite time for singledose and area under the concentration-time curve from time 0-24 h for multiple-dose administration increased 4.3- and 4.1-fold, respectively; peak plasma concentration values increased 4.5- and 4.3-fold, respectively. Mean apparent half-life ranged from 10.75-13.49 h across all doses following single and multiple dose administration. Accumulation ratios for area under the concentration-time curve ranged from 1.478 to 1.669 (peak plasma concentration, 1.488- 1.578). No serious or severe adverse events were reported. Conclusion: The pharmacokinetics of multiple-dose desvenlafaxine 50-200 mg was linear and was able to be predicted from single-dose pharmacokinetics in Korean subjects. Pharmacokinetic parameters were similar to values previously observed in other racial/ethnic populations. There were no new safety findings for desvenlafaxine.

ABSTRACT Aim: Palbociclib (P), a selective oral cyclin-dependent kinase 4/6 inhibitor that blocks G1/S cell cycle progression, is in phase 2 and 3 clinical trials across multiple oncology indications. P has low solubility and high permeability. This completed phase 1 study estimated the effect of food on P bioavailability. Methods: This randomized, open-label, 4-sequence, 4-period crossover study (NCT01904747) in 28 healthy adult volunteers estimated the relative bioavailability of single-dose P 125 mg (free base capsule) administered 30 min after a high fat/calorie meal, 30 min after a low fat/calorie meal, or between 2 moderate fat/standard calorie meals (1 h after/2 h before) versus after fasting ≥10 h overnight (washout: ≥10 d between study periods). No food was allowed ≥4 h postdose (all conditions except moderate fat meal). Pharmacokinetic (PK) samples were collected predose and serially up to 144 h postdose; P concentrations were measured using validated high-performance liquid chromatography tandem mass spectrometry. PK data were analyzed using a non-compartmental approach based on a mixed effects model. Results: Time to maximum P concentration (Tmax) and terminal plasma half-life (t1/2) values were similar across fed and fasted conditions (median Tmax: 8 h, all; mean t1/2: 22.03–23.90 h). Relative to the fasted condition, ratios of adjusted geometric means for high fat, low fat, and moderate fat conditions were 121%, 112%, and 113%, respectively, for AUCinf and 138%, 127%, and 124%, respectively, for Cmax; the slight increase in exposure in the fed versus fasted conditions was driven mainly by a subgroup of subjects (n = 3) with significantly lower exposure in the fasted condition. PK variability (% coefficient of variation) was reduced in the fed (AUCinf, 23%–27%; Cmax, 21%–24%) versus fasted (AUCinf, 39%; Cmax, 73%) conditions. In a supplemental analysis excluding the 3 subjects with significantly lower exposure in the fasted condition, food intake did not affect P exposure, and PK variability was similar across fed and fasted conditions. Conclusions: Overall, P exposure was marginally affected, but PK variability was greatly reduced, in the fed versus the fasted condition. Thus, P should be administered with food. Disclosure: A. Ruiz-Garcia: Employment: Pfizer Inc Stock ownership: Pfizer Inc.; A. Plotka: Employment: Pfizer Stock ownership: Pfizer; S. Pawlak: Speakers’ bureau: Pfizer Employment: Pfizer Stock ownership: Pfizer; M. O'Gorman, S. Nidadavolu and S. Phillips: Employment: Pfizer; M. Kosa: Employment: Contractor at Pfizer (Clinical Assay Group) through Atrium Services. D.D. Wang: Employment: Pfizer Stock ownership: Pfizer.

Background: D is a highly selective irreversible small molecule inhibitor of the HER family of tyrosine kinases in clinical development for NSCLC. This study evaluated the PK and safety of D following a single oral dose in subjects with mild or moderate hepatic impairment. Methods: 25 subjects were enrolled in this phase 1, open-label, parallel group study. Subjects had normal hepatic function (n = 8), or mild (Child-Pugh A; n = 8) or moderate (Child-Pugh B; n = 9) hepatic impairment. D was administered as a single, oral 30 mg dose. PK samples were collected at regular intervals up to 264 hours post-dose and safety was assessed through AE monitoring, physical examination, vital signs, ECGs, and laboratory abnormalities. Analysis of variance was performed on natural log-transformed AUC and Cmax to estimate adjusted mean differences between groups and 90% CIs. These data were exponentiated to produce the adjusted GMR and 90% CI of the ratios. Results: Subjects with normal hepatic function and those with mild impairment showed similar mean D exposure; preliminary GMR (90% CI) vs normal function: 1.01 (0.73–1.38) and 1.03 (0.69–1.53) for AUCinf and Cmax, respectively. In those with moderate hepatic impairment, D exposure was decreased by 15% and 20% for AUCinf and Cmax, respectively (GMR [90% CI] vs normal function: 0.85 [0.62-1.15] and 0.80 [0.55–1.17]). However, the 90% CI was relatively wide and included 1. Similar plasma protein binding of D was observed in the 3 groups. There were no reports of clinically significant treatment-related AEs. Conclusions: Mean D exposure (AUCinf and Cmax) was not altered in subjects with mild or moderate hepatic impairment. Subjects with mild or moderate hepatic impairment may not require D dose reduction. D given as a single 30 mg dose was well tolerated in subjects with mild or moderate hepatic impairment.

There is a potential risk that 5-HT1A receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the combination of the 5-HT1A antagonist lecozotan and the SSRI citalopram in a well-controlled Clinical Pharmacology Unit setting using the Hunter Serotonin Toxicity Criteria (HSTC), a set of validated decision rules featuring neurological and body temperature measurements, to detect any clinically relevant serotonin toxicity. Forty-three young healthy male subjects were randomized, to 2 parallel double-blind treatment groups following a 10-day citalopram 40mg run-in period: citalopram 40mg/lecozotan 10mg or citalopram 40mg/placebo for 9days. Overall, the combined administration of active drugs was well tolerated, however, one subject experienced moderate hyperreflexia, tremor of the hands, and sweating of hands and feet after 3days of combined treatment. The event prompted treatment withdrawal and was regarded as mild serotonin toxicity, as per the HSTC. The onset of the event was around the time of peak plasma concentrations (tmax) of both lecozotan and citalopram, and its time course corresponds to the well-defined PK profile of lecozotan. No evidence of a PK interaction was detected trough lecozotan and citalopram plasma concentrations analysis. The utility of the HSTC in detecting the non-discrete group of symptoms commonly referred to as “serotonin toxicity” was demonstrated in this clinical pharmacology study combining two 5-HT agents in a clinically controlled setting.

Previous reports have described the ectopic expression of substance P binding sites on lymphoid aggregates and small blood vessels in inflammatory bowel disease. In this report, three non-peptide NK-1 receptor antagonists, CP-96,345, RP-67,580, and L-703,606, abolished saturable 125I-Bolton-Hunter substance P binding to the ectopically expressed receptors in frozen sections of surgically resected bowel from five patients with either Crohn's disease or ulcerative colitis. The rank order of affinity was approximately substance P ≈ CP-96,345 ≈ L-703,606 > RP-67,580. These results suggest that: (i) the ectopically expressed substance P binding sites in inflammatory bowel disease are authentic NK-1 receptors, (ii) all ectopically expressed receptors on small blood vessels, and lymphoid aggregates as well as normally expressed receptors on the bowel circular muscle have similar receptor affinities and specificities for substance P and the non-peptide antagonists, and (iii) non-peptide antagonists may be therapeutically beneficial in inflammatory bowel disease by inhibiting the pro-inflammatory effects of substance P acting via the NK-1 receptor.

This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using 11C-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An Emax pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.

BACKGROUND/AIMS Lecozotan is a potent and silent 5-HT1A antagonist being developed for the treatment of cognitive deficits associated with Alzheimer's disease. The objective of this study was to assess the safety, tolerability, and PK of multiple oral doses of Lecozotan in elderly subjects (> 65 yrs old), a population similar to the target patient population. METHODS This was a randomized, double-blind, placebo-controlled study in 16 subjects who received 5 mg q12h of Lecozotan or placebo (12 active, 4 placebo) for 14 days. Safety evaluations included adverse events (AE), vital signs, ECG, and lab tests up to 48 hours after the last dose. A complete PK profile was obtained on days 1 and 14. RESULTS Lecozotan was safe and well tolerated after multiple dosing. Few mild to moderate AEs were recorded in 4 out of 16 subjects. There were no clinically significant changes in vital signs, ECGs, and routine laboratory tests. Lecozotan tmax was < 1 hour and t1/2 was 9 – 11 hours. Steady-state Cl/F was ∼33 mL/h/kg. Steady-state was achieved by day 3 of q12h administration and accumulation ratio was 1.8. Mean steady-state AUC0–12h was within 13% of the mean single-dose AUC0-∞ suggesting reliable multiple-dose predictability from single-dose PK. Cl/F in elderly was ∼ 25% lower in comparison to young subjects. CONCLUSIONS Lecozotan was safe in elderly subjects up to multiple daily doses of 10 mg and the elderly PK profile was characterized by a mild decrease in clearance, which does not justify any dosage adjustment. Clinical Pharmacology & Therapeutics (2005) 79, P68–P68; doi: 10.1016/j.clpt.2005.12.247

BACKGROUND/AIMS To assess the effects of a low-, medium-, or high-fat meal on the relative bioavailability and pharmacokinetics (PK) of desvenlafaxine following administration of desvenlafaxine succinate extended release (DVS). METHODS This was a single-dose, open-label, randomized, 4-period, 4-sequence, crossover, inpatient study. A single oral 200-mg dose of DVS was administered to 33 healthy male and female subjects after an overnight fast (>10 hours), or after the completion of a low-, medium-, or high-fat breakfast on study day 1 of each period. Blood samples were obtained over 72 hours. A model-independent method of PK analysis was used to analyze plasma concentrations of desvenlafaxine. The PK parameters of desvenlafaxine were compared by dosing condition using an analysis of variance for a 4-period crossover study. RESULTS The median Tmax for desvenlafaxine was approximately 6 hours after administration of DVS under fasting conditions and was delayed by about 2 hours when administered with food. Cl/F and t½ values for desvenlafaxine were not altered by administration with food. With the exception of Cmax under high fat conditions, both Cmax and AUC∞ for desvenlafaxine met bioequivalence test criteria (90% confidence interval[CI] within 80% to 125%); the 90% CI for Cmax under high-fat conditions was 108% to 125.05%. CONCLUSION These results suggest that PK should not be a factor in considering whether to administer DVS with or without food. Clinical Pharmacology & Therapeutics (2005) 79, P25–P25; doi: 10.1016/j.clpt.2005.12.089

BACKGROUND/AIMS L, a potent and silent 5HT1A antagonist, is being developed for the treatment of Alzheimer's disease (AD). This study, which used the immediate release (IR) formulation, was conducted to assess L binding to 5HT1A receptors in human brain using PET and WAY-100635 as tracer, in order to guide dose selection for Phase 2 studies with the sustained release (SR) formulation. METHODS A single dose of 0.5, 1, or 5 mg lecozotan-IR was administered to healthy young subjects and a single dose of 5 mg was administered to elderly subjects and AD patients to assess possible binding differences due to age/disease. L Cplasma-receptor occupancy (RO) relationship was described using an Emax pharmacodynamic model by means of a population approach. Based on this model, peak and trough RO were predicted for various regimens of the 2 formulations. RESULTS After single 0.5, 1, and 5 mg doses to young subjects, the average temporal cortex 5-HT1A RO increased in a dose-dependent manner (10%, 18%, 44%, respectively). After a single oral dose of 5 mg lecozotan, maximum RO, seen at tmax of lecozotan, was 44% in young, 63% in elderly and 55% in AD populations. The SR formulation is predicted to produce steady state peak/trough RO of approximately 37%/19%, 57%/36%, and 71%/53% with 2, 5 and 10 mg QD, respectively. CONCLUSIONS These results demonstrate that Lecozotan is predicted to produce similar 5HT1A RO with a QD dose of SR formulation as with a BID dose of IR formulation. Clinical Pharmacology & Therapeutics (2005) 79, P16–P16; doi: 10.1016/j.clpt.2005.12.055