Pharmacokinetics of Oral Pridinol: Results of a Randomized, Crossover Bioequivalence Trial in Healthy Subjects
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International Journal of Clinical Pharmacology and Therapeutics, Vol. 59 – No. 6/2021 (471-477) Pharmacokinetics of oral pridinol: Results of a randomized, crossover bioequivalence trial in healthy subjects Original Maren Richter1, Frank Donath1, Ralph-Steven Wedemeyer2, André Warnke1, 3 3 ©2021 Dustri-Verlag Dr. K. Feistle Andreas Horstmann , and Claudia Peschel ISSN 0946-1965 DOI 10.5414/CP203900 1SocraTec R&D GmbH, Oberursel/Erfurt, 2SocraMetrics GmbH, Erfurt, and e-pub: April 9, 2021 3Strathmann GmbH & Co. KG, Hamburg, Germany Key words Abstract. Objectives: To establish the What is known about this subject bioavailability – bio- relative bioavailability and to assess bio- equivalence – immedi- equivalence of oral, immediate-release tab- – The anticholinergic agent pridinol has ate-release tablet – lets containing pridinol and to determine been used as a muscle relaxant for de- pharmacokinetics the pharmacokinetic properties of the com- cades. – pridinol pound. Methods and materials: In this single- – However, the published literature on the center, open-label, randomized, crossover pharmacology of pridinol is sparse. trial, healthy male and female adult subjects received single doses of the test and refer- – More accessible information on the cha- ence product containing 4 mg pridinol me- racteristics of pridinol, e.g., its pharma- sylate (equivalent to 3 mg pridinol) each cokinetics in humans, is needed. under fasting conditions. For pharmacoki- netic evaluation, blood samples were with- What this study adds drawn until 72 hours post dose. Pridinol in plasma was quantified by validated liquid – This is the first detailed report on the chromatography-mass spectrometry/mass pharmacokinetic properties of pridinol in spectrometry (LC-MS/MS). Adverse events humans, assisting the prescriber to make (AEs) were analyzed descriptively. Results: Of 34 randomized subjects, 33 completed informed treatment decisions. all treatments. The determined pharmaco- – Bioequivalence of two oral, immediate- kinetic parameters were quite similar for release pridinol products was demon- both products, with geometric means for strated. maximum exposure (Cmax) of 29.27 ng/mL (test) and 27.44 ng/mL (reference), reached after 1.00 and 0.90 hours (mean tmax), re- spectively. The extents of bioavailability Introduction (geometric mean AUC0–tlast) were 187.93 h×ng/mL (test) and 183.51 h×ng/mL (refer- Pridinol, a centrally acting muscle relax- ence). Elimination half-lives (T1/2) ranged ant, attenuates polysynaptic reflexes via an from 8.97 to 34.85 hours with comparable anticholinergic mechanism [1, 2]. The com- mean T1/2 of 19.14 hours (test) and 18.85 pound had been used as a muscle relaxant hours (reference). The point estimates of for decades and is available as a single agent the test/reference-adjusted geometric mean for instance in Germany and Italy. However, ratios of AUC0–tlast, Cmax (primary), and the German product (Myoson direct tablets, Received AUC0–∞ (secondary) were 102.54% (90% September 17, 2020; confidence interval: 96.19 – 109.32%), Strathmann, Hamburg, Germany) was with- accepted 106.79% (99.00 – 115.20%), and 102.60% drawn from the market in January 2016 due January 17, 2021 (96.20 – 109.43%), respectively. Overall, 23 to regulatory reasons. Based on the results of subjects experienced 50 AEs; headache and the present study, pridinol-containing tablets Correspondence to dizziness (15 cases each) were most frequent- Claudia Peschel, MD ly reported. Conclusion: Bioequivalence of were again authorized in Germany in De- Strathmann GmbH & both pridinol products was demonstrated in cember 2017 (brand name: Myopridin 3 mg Co. KG, Langengorner terms of rate and extent of absorption. Safety tablets, Strathmann, Hamburg, Germany) for Chaussee 602, 22419 and tolerability were in accordance with the treatment of central and peripheral muscle Hamburg, Germany known AE profile of the drug substance. Claudia.peschel@ spasms, torticollis, lumbago, and general dermapharm.com muscle pain in adults [2]. In 2020, pridinol Richter, Donath, Wedemeyer, et al. 472 tablets were approved based on Myopridin as Drug products reference in further European countries such as the United Kingdom, Poland, and Spain. Clinical trial batches of the test (Myo- Skeletal muscle relaxants are a heteroge- son direct, Strathmann, Hamburg, Germany) nous drug class used for treatment of central and the reference product (Lyseen, Novartis muscle spasms (spasticity), e.g., after stroke, Consumer Health, Origgio, Italy) were man- and peripheral musculoskeletal spasms such ufactured according to good manufacturing as those arising from low back pain [1]. In practice (GMP) standards and were selected the indication spasticity, pridinol adds to the in accordance with European requirements armamentarium of available muscle relax- for bioequivalence trials [9]. The reference ants including tizanidine, baclofen, and tol- product, registered in Italy, was purchased perisone [3, 4, 5]. Of note, in Germany, pridi- from the Italian market. nol is currently – besides methocarbamol [6] Both products were divisible, immedi- – the only approved muscle relaxant for treat- ate-release tablets containing 4 mg pridinol ment of peripheral muscle spasms associated mesylate corresponding to 3 mg pridinol with low back pain [2], a highly debilitating per tablet as active ingredient. The qualita- condition with an estimated prevalence rate tive composition of the test product included between 1.4% and 15.6% [7]. highly dispersed silicon dioxide, hydroge- The published literature on pridinol is nated castor oil, lactose monohydrate, mag- sparse. According to the summary of product nesium stearate, microcrystalline cellulose, characteristics, pridinol reaches its maximum polyvinylpyrrolidone, and talcum. Excipi- plasma concentration within 1 hour after oral ents of the reference product were lactose, administration and is evenly distributed in starch, talcum, and glycerol dibehenate. tissues [2]. It is metabolized primarily via In-vitro dissolution was analyzed ac- cytochrome P450 (CYP) 2C19 and CYP2B6 cording to the Guideline on the Investiga- [internal data] to its main metabolite 4-hy- tion of Bioequivalence [10]. Basket dis- droxypridinol [8]. Pridinol is renally elimi- solution testing (37 °C, 100 rpm, 500 mL) nated as unchanged drug and as glucuroni- at pH 1.2, 4.5, and 6.8 revealed a very dated or sulfoconjugated drug [2]. rapid release with comparable drug re- The primary objective of the present lease rates of 98.5 – 100.4% (test product) study was to assess the bioequivalence of and 98.1 – 99.9% (reference product) after two oral pridinol formulations after single- 15 minutes. dose administration under fasting conditions. The secondary objectives included the deter- mination of pridinol’s pharmacokinetic char- Study conduct acteristics and the assessment of its safety and tolerability. The single-center, open-label, rando- mized (order of treatments), single-dose, crossover trial was conducted from May to Materials and methods July 2016. Study participants In each period of the trial, the subjects were administered either 1 tablet of the test In the study, healthy male or female sub- or reference product in the morning after an jects, aged ≥ 18 years, of Caucasian ethnicity overnight fasting period of 8 hours (no food, were included. The subjects had a body mass no beverages, only water was allowed until index of 18.5 – 30.0 kg/m2 and were non- 1 hour prior to dosing). The use of any sys- smokers or ex-smokers for at least 3 months. temically available medication except hor- Pregnant or breast-feeding women were ex- monal contraceptives was not allowed. Simi- cluded. Furthermore, subjects with contrain- larly, specific foods known to interact with dications to pridinol and/or conditions that metabolizing enzymes (CYP450, P-glycopro- might have an impact on the pharmacoki- tein), e.g., grapefruit/pomelo-containing food netics of the compound were excluded. All or beverages, star fruit-containing food or subjects provided written informed consent beverages, St. John’s wort, Brussels sprouts, before enrollment. or broccoli were not permitted. Pharmacokinetics of oral pridinol 473 Blood samples were collected over 72 Bioanalytical method hours. This time span was considered ade- validation and sample analysis quate to obtain a reliable estimate of the extent of absorption, i.e., the area under the Pridinol in plasma was quantified by curve (AUC) derived from measurements liquid chromatography-mass spectrometry/ was expected to cover at least 80% of the mass spectrometry (LC-MS/MS) after vali- AUC extrapolated to infinity (AUC0–∞). dation according to the Guideline on Bio- Since the elimination half-life of pridinol analytical Method Validation [9]. Diphenidol ranged between 3.89 and 24.99 hours in a hydrochloride served as internal standard. previous pilot study (Strathmann, Study CPA The established lower and upper limits of 139-01, 2002, unpublished), and since indi- quantitation for pridinol were 0.0500 ng/mL vidual values of up to 30.5 hours were known and 50 ng/mL, respectively. Precision (coef- from smaller earlier trials (internal data), the ficient of variation (CV): ≤ 4.5%) and accu- washout phase between the 2 treatment pe- racy (percentage relative deviation from nor- riods lasted 13 days to ensure that the drug mal value (RD): ≤ ± 6.6%) during analysis was virtually completely eliminated from the of the trial samples were in accordance with body prior to subsequent application.