Prediction of Carboxylesterase 1-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models

Abstract

The use of cannabis products has increased substantially. Cannabis products have been perceived and investigated as potential treatments for attention-deficit/hyperactivity disorder (ADHD). Accordingly, co-administration of cannabis products and methylphenidate (MPH), a first-line medication for ADHD, is possible. Oral MPH undergoes extensive presystemic metabolism by carboxylesterase 1 (CES1), a hepatic enzyme which can be inhibited by two prominent cannabinoids, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). This prompts further investigation into the likelihood of clinical interactions between MPH and these two cannabinoids through CES1 inhibition. In the present study, inhibition parameters were obtained from a human liver S9 system and then incorporated into static and physiologically-based pharmacokinetic (PBPK) models for prediction of potential clinical significance. The inhibition of MPH hydrolysis by THC and CBD was reversible, with estimated unbound inhibition constants (K_i,u) of 0.031 and 0.091 µM, respectively. The static model predicted a mild increase in MPH exposure by concurrent THC (34%) and CBD (94%) from smoking a cannabis cigarette and ingestion of prescriptive CBD, respectively. PBPK models suggested no significant interactions between single doses of MPH and CBD (2.5 - 10 mg/kg) when administered simultaneously, while a mild interaction (area under drug concentration-time curve increased by up to 55% and maximum concentration by up to 45%) is likely if multiple doses of CBD (10 mg/kg twice daily) are administered. In conclusion, the pharmacokinetic disposition of MPH can be potentially influenced by THC and CBD under certain clinical scenarios. Whether the magnitude of predicted interactions translates into clinically relevant outcomes requires verification in an appropriately designed clinical study. SIGNIFICANCE STATEMENT: This work demonstrated a potential mechanism of drug-drug interactions between methylphenidate (MPH) and two major cannabinoids (Δ⁹-tetrahydrocannabinol [THC] and cannabidiol [CBD]) not previously reported. We predicted a mild interaction between MPH and THC when the cannabinoid exposure occurred via cannabis smoking. Mild interactions between MPH and CBD were predicted with multiple oral administrations of CBD.

Fig. 1.

Chemical structures of MPH, RA, THC, and CBD and hypothesis of CES1-mediated interactions between MPH and THC/CBD. Dashed lines with flat arrows represent inhibition.

Fig. 2.

Inhibition curves for THC (A) and CBD (B) in time-dependent inhibition study. HLS9 (250 µg/ml) was preincubated with or without cannabinoids for 30 minutes before addition of MPH. The formation rate of metabolite (ritalinic acid) from MPH was expressed as a relative value over the control sample without addition of cannabinoids. Data points represent the mean (±S.D.) of triplicate samples from a single experiment. Lines represent model prediction.

Fig. 3.

Representative analyses of inhibition kinetics and Lineweaver-Burk plots for THC (A1, A2) and CBD (B1, B2). Incubation was conducted using 250 µg/ml HLS9 with combinations of varying concentrations of MPH and cannabinoids. Data were from one of three independent experiments with duplicate samples. Points represent mean values (±S.D.) of duplicate samples.

Fig. 4.

PBPK model simulated and observed concentration-time profiles of MPH after oral administration. The simulated PK profiles were compared with the observed data reported in literature for assessment of model performance. Demographics of the simulated virtual individuals (n = 100) were matched to ones reported in the respective study. Solid lines and shades represent mean and 90% (5^th–95^th) prediction interval of simulated profiles, respectively. Points and error bars represent mean and S.D. of the observed data, respectively. Median values (both simulated and observed) were summarized for the Stage_2017 study.

Fig. 5.

PBPK model simulated and observed concentration-time profiles of CBD after oral administration. The simulated PK profiles were compared with the observed data reported in literature for assessment of model performance. Demographics of the simulated virtual individuals (n = 100) were matched to ones reported in the respective study. Solid lines and shades represent geometric mean and 90% (5^th–95^th) prediction interval of simulated profiles, respectively. Points and error bars represent geometric mean and S.D. of the observed data, respectively.

Fig. 6.

Simulated outcomes of administration of MPH either simultaneously (A) or with a time difference (B) to a single dose of CBD. The IR formulation of MPH (Ritalin) and the prescriptive oral solution formulation of CBD (Epidiolex) were used in simulation. Under the scenarios of simultaneous administration (A), different strengths of CBD dose (2.5–10 mg/kg) were simulated. Under the scenarios of MPH and CBD administered at different time (B), the dose of CBD was fixed at 10 mg/kg. The resulting influence of CBD on the exposure to d-MPH were summarized as ratios of AUC and C_max as compared with MPH administered alone. The ratios were reported in the forms of geometric means and 90% prediction interval of the simulated 100 virtual subjects.

Fig. 7.

Simulated changes in MPH exposure when co-administered with multiple doses of CBD for 7 days. The IR formulation of MPH (Ritalin) and the prescriptive oral solution formulation of CBD (Epidiolex) were used in simulation. In the simulation, MPH was administered twice daily with a time interval of 4 hours between the first and second doses, while CBD (0, 5, and 10 mg/kg) was given every 12 hours. The AUC₂₄ and C_max of d-MPH were summarized on Day 1, 4, and 7. Open circles represent individual parameter values of the simulated 100 virtual subjects. Horizontal bars in the boxplots represent the 5^th, 50^th, and 95^th percentiles of the simulated population.