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 (C) 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 AUC (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.
Xevinapant, an antagonist of Inhibitor of Apoptosis Proteins (IAPs) showed significant improvement in locoregional control at 18 months (LRC18; primary endpoint), overall survival (OS) and progression-free survival (PFS) at an oral dose of 200 mg/day given on days 1-14 every 3 weeks in combination with CRT versus CRT with placebo in a phase II trial in patients with high-risk LA SCCHN (NCT02022098). In the dose escalation (DE) part of NCT02022098, 200 mg/day was the maximum tolerated dose and a trend of dose-response for efficacy in the 100-300 mg/day dose range was observed. The phase III TrilynX study of xevinapant plus CRT in patients with LA SCCHN is currently enrolling (NCT04459715). Here we present the integrated rationale for the recommended phase III dose (RP3D) of xevinapant 200 mg/day based on all available clinical and preclinical data and modeling and simulation (M&S). At the RP3D, ~95% of the patients are projected to have free trough concentrations above in vitro IC50 for cIAP1 degradation (a pharmacodynamic [PD] marker), based on a population (pop) PK M&S. In patients, average free concentration over the dosing interval at RP3D is similar to that associated with maximal efficacy in preclinical SCCHN models. Pop PK/PD M&S suggests that maximal cIAP1 degradation is maintained in PBMCs with 100-200 mg/day doses during the 14-day dosing period, with a trend of dose-response for the partial cIAP1 degradation at the end of the 3-week cycle. Exposure response (E-R) analyses were conducted based on the pooled datasets of DE and randomized parts of study NCT02022098 (n=62 treated with xevinapant). Logistic regressions showed that probabilities of LRC18, overall response, complete response, and the composite safety endpoint of “mucositis and/or dysphagia” increase with increasing exposure (p<0.05). Statistically significant E-R relationships were not discernible for any other evaluated safety endpoints or for PFS, OS, or duration of LRC. However, patients in higher exposure subgroups showed a longer duration of LRC. In summary, integration of preclinical pharmacology, clinical efficacy and safety profiles, clinical PK/PD, popPK, and E-R analyses support the RP3D selection of xevinapant at 200 mg/day administered on days 1-14 every 3 weeks with concomitant CRT, allowing for successive dose reductions to 150 mg and 100 mg for management of toxicities. Citation Format: Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul M. Diderichsen, Huub J. Kleijn, Kosalaram Goteti, Andreas Schroeder, Karthik Venkatakrishnan. Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5424.
e18001 Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, thereby enhancing the efficacy of RT and CRT. Xevinapant 200 mg/d (d1-14, Q3W) + CRT showed clinical benefit vs placebo + CRT in a phase (ph) 2 study of patients (pts) with LA SCCHN (NCT02022098). Exposure-response (E-R) relationships for efficacy and the composite safety endpoint of mucositis and/or dysphagia (AE_MD, a known RT-associated toxicity) were also identified. Two ph 3 studies of 200 mg/d xevinapant (d1-14, Q3W) + RT (XRay Vision; NCT05386550) or CRT (TrilynX; NCT04459715) followed by xevinapant monotherapy (MT) in pts with LA SCCHN are ongoing. We leverage the MOA of xevinapant to confirm RP3D strategy. Methods: Results from clinical and preclinical studies and quantitative pharmacology modeling were integrated. Results: Updated analyses of NCT02022098 data show an association between complete response (CR) and AE_MD in both treatment arms; AE_MD was the only AE with identified E-R relationship out of 13 AEs tested. In the xevinapant arm, the CR+AE_MD+ group had the highest median AUC but it overlapped with other groups (CR-AE_MD+, CR+AE_MD-, CR-AE_MD-) which all had similar AUCs. These data suggest that AE_MD is related to the RT-enhancing MOA of xevinapant and that decoupling efficacy from AE_MD incidence by exposure modulation is not feasible. Intermittent dosing for xevinapant was designed for recovery from epithelial toxicities considering the turnover of mucosal cells. In a human breast cancer mouse model, cIAP1 degradation with the intermittent regimen (100 mg/kg Q3D) at the end of the dosing interval was ~50% compared with the continuous one (30 mg/kg QD) expected to maintain maximal (max) cIAP1 degradation, but showed similar efficacy. This suggests continuous max cIAP1 degradation may not be required for efficacy, consistent with RT-enhancing MOA. Based on population PKPD modeling, at the RP3D for xevinapant max cIAP1 degradation was achieved during the dosing period; 91% of pts had at least 50% suppression at the end of the cycle. Xevinapant MT cycles are supported by enhanced anti-tumor activity with extended MT dosing following xevinapant/ RT cycles in MC38 syngeneic mouse model. Food-agnostic dosing is supported by similar AUCs observed in fed and fasted conditions. A human ADME study showed that urinary excretion is a minor elimination pathway, supporting no dose adjustment for pts with moderate renal impairment. Conclusions: Integrated assessment of all available clinical and nonclinical data supports the proposed RP3D strategy for xevinapant combined with RT or CRT, selected to maximize efficacy while minimizing potential adverse events and cumulative toxicity. Clinical trial information: NCT02022098 .
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