A perspective on the physicochemical and biopharmaceutic properties of marketed antiseizure drugs—From phenobarbital to cenobamate and beyond

Abstract

The success rate from first time in man to regulatory approval of central nervous system (CNS) drugs is lower than the overall success rate across all therapeutic indications (eg, cardiovascular, infectious diseases). To understand the reasons for drugcandidate failure and to capture trends in antiseizure drug (ASD) design, we have analyzed the physicochemical and biopharmaceutical properties of marketed ASDs in comparison with new ASDs in development. Our comparative analysis included molecular weight (MW), logP, polar surface area (PSA), the "Lipinski rule of five," and the CNS Multiparameter Optimization (MPO) score. LogP is the logarithm of a drug-partition coefficient (P) between n-octanol and water. PSA is the molecule's surface sum of its polar atoms. ASDs' biopharmaceutical properties were classified according to their water solubility, permeability, and route of elimination as outlined by the Biopharmaceutics Classification System (BCS) and Biopharmaceutics Drug Disposition Classification System (BDDCS). For old ASDs (1912-1990), logP, PSA, and CNS MPO values ranged between 0.4 and 2.8, 37 and 87 Å 2 , and 4.4 and 6.0, respectively. For second-generation ASDs (1990-2008), PSA values ranged between 39 and 116 Å 2. However, logP values showed a difference between the lipophilic (logP = 0.3-3.21) and hydrophilic (logP = −0.6 to −2.16) ASDs. For third-generation ASDs (2008-2020), logP and PSA ranged between 0.3 and 3.5 and between 57 and 76 Å 2 , respectively. The mean CNS MPO scores of all marketed ASDs were similar, ranging between 4.9 and 5.4, and were similar to those of the ASDs in development (3.5-5.8). Most ASDs belong to BCS and BDDCS classes 1 and 2. MW, logP, CNS MPO score, and PSA assess lipophilicity and correlate with antiseizure activity. To succeed, a new small-molecule ASD must have MW < 375 and PSA < 140Å 2 , belong to BCS and/or BDDCS class 1 or 2, and obey the Lipinski rule of five: logP < 5, MW < 500, and <5 and <10 of hydrogen-bond donors and acceptors, respectively. The similarity in the MW, logP, and PSA values of marketed and new drugs in development indicates a conservative trend in ASD design.

Towards Better Delivery of Cannabidiol (CBD)

“…The oil/water partition coefficient (Log P ) describes a drug preference which exists either in the water or oil part of a solution; higher Log P values mean more of the drug will be distributed in the oil part of the solution. Due to the highly lipophilic nature of CBD (Log P 6.3) [ 11 ], it is most commonly supplied as an oil or alcoholic formulation either in soft-gel capsules, liquid solution, sublingual drops, or as an oromucosal spray [ 12 ]. Studies examining oral and oromucosal delivery of CBD and THC at equimolar concentrations in humans show high inter/intra-individual variability [ 13 , 14 ].…”

Chemical synthesis, inhibitory activity and molecular mechanism of 1-deoxynojirimycin–chrysin as a potent α-glucosidase inhibitor

“…log P values between 0.5 and 3.0 have contributed to the absorption and distribution for a drug candidate. 34 As shown in Table 1, compound 6 exhibited the best lipophilicity with an experimental log P of 2.61 AE 0.06 among compounds 4-6, which might be related to the presence of chrysin and undecane chain.…”

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re‐appraisal based on analysis of generic ASM products approved in Europe

“…26,29,30 Among second-generation ASMs, brivaracetam, cenobamate, lacosamide, lamotrigine, levetiracetam, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide are classified as BCS Class 1, whereas gabapentin and rufinamide are classified as BCS Class 3. 31 Although the number of drugs potentially qualifying for BCS-based biowaivers is relatively large, in practice this category of biowaivers has been applied relatively infrequently and only for a limited number of drugs, probably due to some ambiguities in relevant criteria and uncertainties concerning the applicability of a biowaiver within pharmaceutical companies and regulatory authorities. [32][33][34] For example, among 46 generic products approved through the European Medicines Agency (EMA)'s centralized procedure in 2016-2017, only 4 were granted a BCS-based biowaiver, one of which was a lacosamide product.…”

“…These biowaivers may apply to immediate‐release oral dosage forms of drugs, which exhibit high aqueous solubility and either high permeability (BCS Class 1) or low intestinal permeability (BCS Class 3), provided that additional stringent specific conditions are met 26,29,30 . Among second‐generation ASMs, brivaracetam, cenobamate, lacosamide, lamotrigine, levetiracetam, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide are classified as BCS Class 1, whereas gabapentin and rufinamide are classified as BCS Class 3 31 …”