No abstract

Introduction There is a large variation in cannabidiol (CBD) pharmacokinetics and little information on its bioavailability. This study aims to establish the CBD dose‐exposure relationship and to evaluate the effects of dosage forms, food, and doses on CBD absorption. Methods Single‐dose (range: 5–6000 mg) CBD plasma concentration‐time profiles administered as oral solution (OS), oral capsule (OC), or oromucosal spray/drop (OM) from healthy volunteers were extracted from 15 published clinical studies. A dose‐exposure proportionality assessment was performed, and a population‐based meta‐analysis of CBD pharmacokinetics and systemic bioavailability was conducted with a nonlinear mixed‐effects modeling. A three‐compartment model with a Weibull or zero‐order absorption model was used to describe CBD disposition and absorption kinetics. Dosage form, food, and dose were assessed for covariation. Results Oral solution CBD exposures increased less than proportionally with doses of 750 mg or greater, and bioavailability (6.5% at 3000 mg) decreased with increasing dose. The bioavailability of OC (5.6%) and fed‐state OM (6.2%) were similar, whereas it was lower in fasted‐state OM (0.9%). The Weibull absorption model best described OS, OC, and fed‐state OM profiles. The slowest absorption rate was observed in OS, resulting in a time of maximum concentration of 4.75 hours, followed by fed‐state OM (3.13 hrs) and OC (2.1 hrs). The absorption kinetics of fasted‐state OM was best described by a zero‐order absorption for the duration of 1.71 hours. Conclusion The effects of doses, dosage forms, and feeding status on CBD pharmacokinetics were quantified and should be taken into consideration for dose optimization.

No abstract

Trans -3,5,4′-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES – the 3- and 4′ monosulfates (R3S and R4′S), and the 3- and 4′ monoglucuronides (R3G and R4′G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC-MSn assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.

Circulating angiogenic factors (CAF) like vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and sVEGFR2 have potential as biomarkers for antiangiogenic therapy. The interpretation of changes in CAF is complicated by the dynamic nature of the tumor and host cells emanating CAF in response to VEGF pathway inhibition. We developed a systems pharmacology model of anti-VEGF agents to investigate CAF modulation by tumor and host cells, and the relationship between overall CAF changes in response to sunitinib and antitumor efficacy. This model distinguishes between the tumor cells' contributions from tumor-independent response to therapy and total plasma CAF correlating with antitumor activity. Altered VEGF is more likely to serve as a useful biomarker reflecting tumor responses in cancer patients whose pretreatment VEGF is higher than baseline VEGF in healthy subjects. Our findings provide a mechanistic insight into tumor modulation of angiogenic molecules, and may explain the inconsistent results found in previous biomarker studies.

Introduction: In traditional pharmacokinetic (PK) bioequivalence analysis, two one-sided tests (TOST) are conducted on the area under the concentration-time curve and the maximal concentration derived using a non-compartmental approach. When rich sampling is unfeasible, a model-based (MB) approach, using nonlinear mixed effect models (NLMEM) is possible. However, MB-TOST using asymptotic standard errors (SE) presents increased type I error when asymptotic conditions do not hold. Methods : In this work, we propose three alternative calculations of the SE based on i) an adaptation to NLMEM of the correction proposed by Gallant, ii) the a posteriori distribution of the treatment coefficient using the Hamiltonian Monte Carlo algorithm, and iii) parametric random effects and residual errors bootstrap. We evaluate these approaches by simulations, for two-arms parallel and two-periods two-sequences cross-over design with rich (n=10) and sparse (n=3) sampling under the null and the alternative hypotheses, with MB-TOST.Results: All new approaches correct for the inflation of MB-TOST type I error in PK studies with sparse designs. The approach based on the a posteriori distribution appears to be the best compromise between controlled type I errors and computing times.Conclusion: MB-TOST using non-asymptotic SE controls type I error rate better than when using asymptotic SE estimates for bioequivalence on PK studies with sparse sampling.

Summary The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis (NCA) followed by two one-sided tests (TOST). In this regard, the PK parameters area under the curve (AUC) and $C_{\max}$ are obtained for both treatment groups and their geometric mean ratios are considered. According to current guidelines by the U.S. Food and Drug Administration and the European Medicines Agency, the formulations are declared to be sufficiently similar if the $90\%$ confidence interval for these ratios falls between $0.8$ and $1.25 $. As NCA is not a reliable approach in case of sparse designs, a model-based alternative has already been proposed for the estimation of $\rm AUC$ and $C_{\max}$ using nonlinear mixed effects models. Here we propose another, more powerful test than the TOST and demonstrate its superiority through a simulation study both for NCA and model-based approaches. For products with high variability on PK parameters, this method appears to have closer type I errors to the conventionally accepted significance level of $0.05$, suggesting its potential use in situations where conventional bioequivalence analysis is not applicable.

Targeted therapies have become an important therapeutic paradigm for multiple malignancies. The rapid development of resistance to these therapies impedes the successful management of advanced cancer. Due to the redundancy in angiogenic signaling, alternative proangiogenic factors are activated upon treatment with anti-VEGF agents. Higher doses of the agents lead to greater stimulation of compensatory proangiogenic pathways that limit the therapeutic efficacy of VEGF-targeted drugs and produce escape mechanisms for tumor. Evidence suggests that dose intensity and schedules affect the dynamics of the development of this resistance. Thus, an optimal dosing regimen is crucial to maximizing the therapeutic benefit of antiangiogenic agents and limiting treatment resistance. A systems pharmacology approach using multiscale computational modeling can facilitate a mechanistic understanding of these dynamics of angiogenic biomarkers and their impacts on tumor reduction and resistance. Herein, we discuss a systems pharmacology approach integrating the biology of VEGF-targeted therapy resistance, including circulating biomarkers, and pharmacodynamics to enable the optimization of antiangiogenic therapy for therapeutic gains.