Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Tobacco smoke exposure enhances reward sensitivity in male and female rats.

RATIONALE: Systemic administration of the tobacco smoke constituent nicotine stimulates brain reward function in rats. However, it is unknown if the inhalation of tobacco smoke affects brain reward function. OBJECTIVES: These experiments investigated if exposure to smoke from high-nicotine SPECTRUM research cigarettes increases reward function and affects the rewarding effects of nicotine in adult male and female Wistar rats. METHODS: Reward function after smoke or nicotine exposure was investigated using the intracranial self-stimulation (ICSS) procedure. A decrease in reward thresholds reflects an increase in reward function. In the first experiment, the rats were exposed to tobacco smoke for 40 min/day for 9 days, and the rewarding effects of nicotine (0.03-0.6 mg/kg) were investigated 3 weeks later. In the second experiment, the dose effects of tobacco smoke exposure (40-min sessions, 1-4 cigarettes burnt simultaneously) on reward function were investigated. RESULTS: Tobacco smoke exposure did not affect the nicotine-induced decrease in reward thresholds or response latencies in male and female rats. Smoke exposure lowered the brain reward thresholds to a similar degree in males and females and caused a greater decrease in latencies in females. There was a positive relationship between plasma nicotine and cotinine levels and the nicotine content of the SPECTRUM research cigarettes. Similar smoke exposure conditions led to higher plasma nicotine and cotinine levels in female than male rats. CONCLUSION: These findings indicate that tobacco smoke exposure enhances brain reward function but does not potentiate the rewarding effects of nicotine in male and female rats.

Pharmacokinetic and Pharmacodynamic Characterization of Tetrahydrocannabinol-Induced Cannabinoid Dependence After Chronic Passive Cannabis Smoke Exposure in Rats.

Introduction: Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation. The goal of the current study was to develop a rat model to characterize the pharmacokinetics (PKs) of THC after cannabis smoke inhalation, and to determine if chronic cannabis smoke inhalation leads to the development of cannabis dependence. Materials and Methods: For the PK study, male Wistar rats were administered THC intravenously (1 mg/kg) or exposed to smoke from 5 or 10 sequentially smoked cannabis cigarettes (5.3% THC) in an automated smoking machine. Plasma samples were collected from 10 min to 10 hours post smoke exposure (or intravenous administration) and analyzed using liquid chromatography-mass spectrometry to characterize the PK of THC. A three-compartment PK model was used to characterize the PKs. In a separate study, three groups of male Wistar rats were trained in an intracranial self-stimulation (ICSS) procedure, and exposed to smoke from burning 5 or 10 cannabis cigarettes (or clean air control conditions), 5 days/week for 4 weeks. Discussion and Conclusions: Across exposure days, the change from baseline in ICSS thresholds for cannabis smoke-exposed groups was significantly lower and response latencies were significantly faster in the cannabis smoke-exposed groups compared to controls, suggesting that chronic cannabis smoke exposure has rewarding properties. Acute administration of the CB1 receptor antagonist rimonabant (0.3, 1.0, 3.0 mg/kg) induced a dose-dependent increase in ICSS thresholds in the smoke-exposed rats, suggestive of dependence and withdrawal. Finally, an effect compartment PK-pharmacodynamic model was used to describe the relationship between THC concentrations and changes in ICSS thresholds after cannabis smoke exposure.

Simultaneous quantification of cannabinoids tetrahydrocannabinol, cannabidiol and CB1 receptor antagonist in rat plasma: An application to characterize pharmacokinetics after passive cannabis smoke inhalation and co-administration of rimonabant.

A highly sensitive and selective liquid chromatography-tandem mass spectrometry method for the determination of tetrahydrocannabinol (THC), cannabidiol, and rimonabant in rat plasma was developed. Analytes and the internal standard were extracted from plasma using a combination of protein precipitation followed by liquid-liquid extraction. Chromatographic separation was done using Waters Symmetry C18, 4.6 × 150 mm, 5 um column using 10 mm ammonium formate buffer and methanol. The total run time was 6 min, and separation was achieved using isocratic elution at a flow rate of 1 mL/min using a 10:90 (aqueous: organic) ratio. The ionization of the analytes was optimized using electrospray ionization in positive mode, and multiple reaction mode was used for this analysis. This method showed linearity from 0.1 to 100 ng/ml for all the analytes and was validated according to FDA Bioanalytical Method Validation Guidance in terms of accuracy, precession, linearity, stability, matrix effect, recovery, and stability. This method was successfully applied to characterize the pharmacokinetics of THC in rats after continuous passive smoke exposure for 50 min when rimonabant was co-administered with cannabis smoke. Maximum concentration (Cmax) for THC was observed immediately after rats were removed from the exposure chamber (10 min post completion) which declined with a terminal half-life of 3.7 h and clearance was calculated to be 1.1 (L/h). Rimonabant (i.p) at a dose of 3 mg/kg was rapidly absorbed and maximum concentration (Cmax) was seen at 11 min which declined with a terminal half-life of 5.4 h and clearance was calculated to be 2.0 (L/h). Exposure AUCinf (h* µg/L) for THC and rimonabant were 13.9 and 457.6 respectively. As this method was highly sensitive and required only 50 µL of plasma, it is applicable in rodent models that assess the exposure-response relationships of these drugs.