Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate

Abstract

Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the Food and Drug Administration, World Health Organization and European Medicines Agency, taking the degradation at some pH values into consideration. Together with solubility and permeability data for cephalexin monohydrate from the literature, it was demonstrated to be a Biopharmaceutics Classification System Class 1 drug. The pharmacokinetic behavior, results of bioequivalence studies published in the literature, as well as the therapeutic uses, potential toxicity and potential excipient effects on bioavailability were also assessed. Cephalexin has a wide therapeutic index and no bioequivalence problems have been reported. Dissolution studies were run under Biopharmaceutics Classification Systemebiowaiver conditions for the pure drug and 2 generic formulations available on the German market. Considering all relevant aspects, it was concluded that a biowaiver-based approval for products containing cephalexin monohydrate as the single active pharmaceutical ingredient is scientifically justified, provided that well-established excipients are used in usual amounts and that both test and reference dosage forms meet the guideline criteria of either "rapidly dissolving" or "very rapidly dissolving."

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

“…Cephalexin, a BCS Class I drug, has high intestinal permeability due to active uptake across the apical membrane of enterocytes via the proton-coupled oligopeptide transporter PEPT1. Variations in the expression of PEPT1 in vitro and in vivo (i.e., Caco-2 cells, human duodenum, and rat jejunum) are correlated with differences in the permeability of cephalexin ( 46 ). Hypothetically, excipients that have the potential to modulate PEPT1 activity or expression could affect the extent of absorption of cephalexin and would be important to consider during formulation development.…”

“…Similarly, in vitro and in situ experiments have shown the excipient caprylocaproyl macrogolglycerides to enhance cephalexin transport. However, these experiments fail to emulate the in vivo human environment that includes active transport and fail to consider an already high permeability of cephalexin ( 46 ).…”

Formulation of Self-Nanoemulsifying Drug Delivery System of Cephalexin: Physiochemical Characterization and Antibacterial Evaluation

“…It was also found to be effective against Escherichia coli [3]. It is listed as a key access antibiotic in the World Health Organization's essential drug list and it is used as a second choice drug in the form of oral delivery for the effective treatment of chronic obstructive pulmonary disease (COPD), pharyngitis, skin, and soft tissue infections [4]. It is a viable alternative to penicillin for patients with penicillin hypersensitivity [5].…”

Optimization of solubility studies performed in the context of BCS biowaiver monographs

“…molecular structure, indication, therapeutic index, toxicity) and with respect to its physicochemical and pharmacokinetic properties (physicochemical properties could include solid and especially polymorphic forms, stereochemistry, acidic/basic properties, partition/distribution coefficient, solubility and stability, while pharmacokinetic properties comprise absorption, bioavailability, permeability, distribution, metabolism, and elimination). 30,31 Additionally, information on existing dosage forms and their performance (bioequivalence/bioinequivalence reports, dissolution results, and excipients) should be included. 30,31 Whereas at the beginning of the biowaiver project, data for solubility were extracted solely from the literature and discussed in terms of their physiological relevance, 28 a lack of solubility data at pH values of interest is now addressed by additional solubility studies.…”

“…30,31 Additionally, information on existing dosage forms and their performance (bioequivalence/bioinequivalence reports, dissolution results, and excipients) should be included. 30,31 Whereas at the beginning of the biowaiver project, data for solubility were extracted solely from the literature and discussed in terms of their physiological relevance, 28 a lack of solubility data at pH values of interest is now addressed by additional solubility studies. 29 Dissolution data of the API and -if possible -reference and generic products can also be generated and reported in the monograph.…”