Kevser Sevim 1, Shriram Pathak 1,3, Paolo Mio 2, Stefano Biondi 2
1 Quotient Sciences (Nottingham, United Kingdom), 2 Recordati Industria Chimica E Farmeceutica (Milan, Italy), 3 Eisai Europe Ltd (Hatfield, United Kingdom)
Objectives:
Methocarbamol is a skeletal muscle relaxant that acts by inhibiting polysynaptic reflexes in the spinal cord and subcortical areas. Methocarbamol is a BCS Class I compound exhibiting rapid absorption, and short elimination half‑life, necessitating frequent dosing regimen in patients. A mechanistic Physiologically Based Pharmacokinetic (PBPK) model was constructed using GastroPlus® and subsequently verified using several published clinical studies with immediate‑release (IR) formulations, enabling robust characterization of the compound’s ADME profile. Once validated, the model was leveraged to delineate the target product profile (TPP) for the 1500 mg IR “reference regimen” administered three times daily (TID). The objectives of this work were: (i) to design a twice‑daily (BID) multiparticulate immediate‑ plus modified‑release (IR+MR) formulation capable of achieving bioequivalence to the established 1500 mg TID IR target product profile, and (ii) to establish a robust formulation design space that accounts for uncertainties in parameters governing lower GI absorption and the effect of modified release rate on drug PK.
Methods:
A series of published clinical studies informed model development, with datasets [1,2] used to refine key PBPK parameters such as permeability and clearance, and independent datasets [3–5] supporting external validation. A PBPK model was developed using GastroPlus™ v9.8.3 (SimulationsPlus, Inc.). Prediction errors (PE) of Cmax and AUC were compared between model predicted and observed data. Hypothetical IR+MR multiparticulate dissolution profiles were generated within a ≤2250 mg total BID dose constraint and assessed for equivalence to TID reference targets (C30min, Cmax, AUC, Cmin) using ±20% acceptance bounds. To explore the design space, “edge‑of‑failure” simulations were conducted across a wide range of MR release durations (T90% 2–10 h) and IR:MR dose ratios. Optimal formulation combinations identified from these simulations were subsequently stress‑tested by varying key uncertain model parameters, including colonic absorption and MR formulation type (dispersed vs. integral). Outputs from the full simulation set were then used to propose a two‑dimensional design space defined by dose and MR release rate.
Results:
A PBPK model for methocarbamol was successfully built and validated against IR PK profiles, with prediction errors for both Cmax and AUC within the 30% threshold. “Edge‑of‑failure” simulations were performed to assess sensitivity to dose ratio (IR:MR) and MR release rate. These analyses indicated a suitable MR release window of T90% ~3-9 h, with robust PK performance across this range. At T90% ≈4.5 h, simulations showed that an IR fraction ≥1200 mg (>53% of the total dose) is required to match key metrics, including C30min, Cmax, AUC, and Cmin, within ±20% of IR reference, establishing the IR contribution target for the multiparticulate (IR + MR prototype) formulation.
As part of the covariate analysis, the MR formulation type (dispersed vs. integral) was evaluated, and its impact on exposure was minimal, yielding <1% difference in AUC between formulations. Colonic absorption emerged as a key sensitivity factor, with a 10‑fold reduction causing a ~12% drop in fraction absorbed (Fa), reinforcing the importance of designing a formulation space robust to GI variability. To mitigate uncertainty in lower‑GI absorption and enable dose‑adjustment flexibility during clinical evaluation, the design space was expanded to 2500 mg rather than limiting it to 2250 mg. A two‑dimensional IR+MR design space was established, defined by: Total IR+MR dose: ≤2500 mg (500 mg < IR ≤ 1500 mg) and MR T90% release times: 3–12 h.
Conclusion:
The verified PBPK model predicted clinical IR PK reasonably very well and supported prospective evaluation of MR formulation designs. Simulations demonstrated that a ≥60% IR fraction in the BID dose is required to achieve TID‑equivalent exposure. Overall, PBPK‑guided development offered a robust framework for optimising Methocarbamol MR regimens and informing formulation strategy early in development. A resilient design space capable of accommodating GI variability- supports formulation flexibility, clinical feasibility, and de‑risks MR development.
References:
[1] Schlegelmilch et al. (2009), Arzneimittelforschung, 59(05), 238-242.
[2] Sica et al. (1990), European journal of clinical pharmacology 39.2 (1990): 193-194.
[3] Zha et al. (2010), Journal of Chromatography B, 878(9-10), 831-835.
[4] Forist et al. (1971), Journal of Pharmaceutical Sciences, 60(11), 1686-1688.
[5] Alessi Severini (1993), Doctoral dissertation, University of Alberta https://ualberta.scholaris.ca/items/005cb125-6b2f-44f6-84a4-3b30a04bce27.
Reference: PAGE 34 (2026) Abstr 12057 [www.page-meeting.org/?abstract=12057]
Poster: Methodology - Study Design