Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Mefloquine Hydrochloride
Section snippets
INTRODUCTION
A biowaiver monograph of mefloquine hydrochloride based on literature data together with some additional experimental data is presented. The risks of basing a bioequivalence (BE) assessment on in vitro rather than in vivo study results for the approval of new immediate release (IR) solid oral dosage forms (so-called “biowaiving”) containing mefloquine hydrochloride, including both reformulated products and new multisource drug products, are evaluated under consideration of its biopharmaceutical
Name
Mefloquine25 (INN); mefloquine hydrochloride (INNM). Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the chemical name of DL-erythro-α-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol-hydrochloride.25 Its two enantiomers are (9R,10S)-(+)-α-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol-hydrochloride and (9S,10R)-(−)-α-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol-hydrochloride. According to IUPAC nomenclature it is termed (R,S)-erythro
Solubility
The solubility of mefloquine hydrochloride is reported to range from very slightly soluble55 to slightly soluble56 in water at room temperature. To investigate the solubility properties of mefloquine hydrochloride according to the Biopharmaceutics Classification System (BCS), additional solubility determinations in water and aqueous buffer media were performed.a The solubility data were obtained at 37°C using a standard shake-flask method. The results are shown in Table 1 and demonstrate that
Absorption and Bioavailability
Since intravenous (i.v.) formulations of mefloquine hydrochloride cause severe venous irritation at the injection site, there is no i.v. dosage form of mefloquine hydrochloride available on the market.75., 76., 77. Therefore, it has not been possible to determine the absolute oral BA of mefloquine hydrochloride.29,31,76
The pharmacokinetic properties of mefloquine have been studied by Desjardins et al.75 using single oral doses of 250, 500, 1000, and 1500 mg. The results of this study indicate a
Bioequivalence
Several studies have demonstrated that the European mefloquine products Lariam® and Mephaquin® are not bioequivalent.58,83 Weidekamm et al.58 performed pharmacokinetic studies of Lariam® and Mephaquin® tablets in 18 healthy volunteers. Statistical evaluation of the pharmacokinetic parameters demonstrated that these two products are not bioequivalent and differences in clinical responses cannot be excluded.58 Moreover, a study in 19 Thai patients with acute uncomplicated P. falciparum malaria
Solubility
The solubility studies of mefloquine hydrochloride published in the literature were not performed under the conditions specified for BCS classification. Results from additional, BCS-conforming solubility measurements indicate that the D/S ratios for the maximum available dosage strength (274.09–275 mg mefloquine hydrochloride) lie between 141 and 908 mL over the pH range 1.0–7.5. The highest solubility of mefloquine hydrochloride was measured at pH 4.5. At lower pH conditions, a common-ion
CONCLUSIONS
Due to the lack of reliable permeability data and the failure to meet the highly soluble criterion, mefloquine hydrochloride cannot yet be assigned conclusively to a BCS Class: it could belong to either BCS Class II or IV. Therefore, a biowaiver currently is not justified for new multisource products or for the re-approval of existing drug products after extensive variations in the formulation and/or manufacturing process, that is, SUPAC level 388 or EU type II variations.95 Small changes may
ACKNOWLEDGEMENTS
Kik Groot, RIVM, is acknowledged for producing Table 3. We also thank K. Ahmad, S. Hilbert, and R. Roosen for their assistance in the laboratory.
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Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine
2014, International Journal for Parasitology: Drugs and Drug ResistanceCitation Excerpt :In 2013, European regulators updated the drug’s core safety profile to warn that symptoms of polyneuropathy developing during mefloquine use were associated with risk of an irreversible neurological condition (Bundesinstitut für Arzneimittel und Medizinprodukte, 2013), and FDA updated the U.S. product labeling with a boxed warning that other neurological effects including vertigo and loss of balance could be permanent in some cases (Arznei-Telegramm, 2013b; McGuire and Wilson, 2013). Originally developed by the U.S. military and first licensed in Europe over a quarter century ago by F. Hoffmann-La Roche as Lariam® (Croft, 2007a), the innovator product was recently withdrawn from the U.S. market without explanation (Strauch et al., 2011). Generic formulations of mefloquine remain recommended in the U.S. (Centers for Disease Control and Prevention, 2013), but are decreasingly prescribed for the drug’s original antimalarial indications (LaRocque et al., 2012; Kersgard and Hickey, 2013).
The impact of the EMA change in definition of "dose" on the BCS dose-solubility ratio: A review of the biowaiver monographs
2014, Journal of Pharmaceutical SciencesCitation Excerpt :The D/S ratio of diclofenac, mefloquine, and rifampicin already exceeded the 250 mL using the 2001 EMEA definition of dose, consistent with their classification according to the US FDA and WHO criteria. Therefore, the increase in the dose associated with the new definition leads to the D/S ratio exceeding the criterion by an even wider margin: the BCS classification of these API is thus not affected.23-26 Although amitriptyline did not meet the criterion for highly soluble at pH 7.5 (US FDA criterion) at the highest dose strength, it had been decided to make a positive biowaiver recommendation based on the high solubility at pH values up to 6.8 and the risk analysis.
Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report
2012, Travel Medicine and Infectious DiseaseCitation Excerpt :By 2008, following reports of persistent vertigo lasting as long as 12–18 months,11,12 the U.S. product insert was updated to warn that in “a small number of patients, dizziness and loss of balance have been reported to continue for months after mefloquine has been stopped”.13 Notwithstanding continued claims of safety, in 2009 the innovator product (Lariam®, F. Hoffman-La Roche) was withdrawn from the U.S. market,14 and the U.S. military sharply curtailed the use of mefloquine in chemoprophylaxis, returning to a policy of first-line doxycycline use,1 the drug of choice prior to mefloquine's licensure.15 Writing in the 2012 CDC Yellow Book, U.S. military authors conceded that the neuropsychiatric side effects of the drug made “continued routine use of mefloquine less desirable”.16
Biowaiver monographs for immediate-release solid oral dosage forms: Primaquine phosphate
2012, Journal of Pharmaceutical SciencesCitation Excerpt :The risk–benefit analysis includes a consideration of the probability of an incorrect biowaiver decision as well as the consequences of an incorrect decision in terms of public health and individual patient risks. Biowaiver monographs have already been published for various APIs.1,5–25 These monographs are also available online on the International Pharmaceutical Federation's website (www.fip.org/bcs_monographs).
Investigating channel blockers for the treatment of multiple sclerosis: Considerations with mefloquine and carbenoxolone
2012, Journal of Neuroimmunology
This article reflects the scientific opinion of the authors and not necessarily the policies of regulating agencies, the International Pharmaceutical Federation (FIP), and the World Health Organization (WHO).
- a
Studies performed at the Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany, using Mefloquine hydrochloride ≥98% pure, lot 060099U00, from Roche Diagnostics GmbH, Mannheim, Germany. No information was available on the polymorphic form.
- b
Studies performed at the Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany, with Lariam, Roche, Germany, Lot B114312 and Mephaquin, Mepha Pharma AG, Switzerland, Lot 0752105.