Pharmacokinetics of Oral Pridinol: Results of a Randomized, Crossover Bioequivalence Trial in Healthy Subjects

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

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 bioequivalence – 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 pharmacokinetic 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), respectively. 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. pre-defined acceptance limits [3]. The long- Testing for bioequivalence (primary term stability at ≤ –20 °C of 58 days suffi- objective) was performed considering ciently covered the longest period for sample AUC0–tlast and Cmax. Secondary pharmacoki- storage of 38 days from the first blood sample netic metrics as well as safety and tolerabili taken until the last sample analyzed. Like- ty of the products were investigated descrip- wise, handling of the plasma study samples tively. Standard safety measures comprised until measurement was performed within the vital signs and clinical laboratory parameters validated stability time span of 6 hours at assessed prior to inclusion (screening) and at room temperature. The incurred sample re- the end-of-trial examination. Adverse events analysis (ISR) passing rate of 87.5% fulfilled (AEs) within the study (spontaneously re- the pre-defined criterion of acceptance [3]. ported or upon questioning) were assessed descriptively. The clinical trial was conducted in ac- Pharmacokinetic cordance with the Declaration of Helsinki and statistical analysis (version 2013), ICH-GCP guidelines (The International Council for Harmonisation of Based on internal results from a previ- Technical Requirements for Pharmaceuti- ous clinical trial comparing 4 mg pridinol cals for Human Use – Good Clinical Prac- mesylate-containing products, intra-indi- tice), and the requirements of the German vidual variabilities of ~ 25% for both AUC Medicinal Products Act (EudraCT no. 2016- and Cmax were estimated. Setting an α of 5%, 001036-35). The trial was approved by the considering an apparent ratio of means be- Ethics Committee of the Thuringian Medical tween test (T) and reference (R) products of Board. µT/µR of 0.95 – 1.05 and acceptance criteria for bioequivalence of 80.00 – 125.00% [10], 28 eligible subjects were needed to achieve Blood samples and preparation a power of 80%. Due to the limited database and to compensate for potential dropouts, 34 Blood samples (4.9 mL) for concentra- subjects were randomized. tion measurement of pridinol were with- Pharmacokinetic calculations were made drawn within 1.0 hour prior to dosing as using non-compartmental analysis in Phoe- well as 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, nix WinNonlin, Version 6.3 (Certara Inc. 12, 24, 36, 48, 60, and 72 hours post dosing Princeton, NJ, USA). The primary pharma- (17 samples per subject and period) and col- cokinetic parameters were AUC0–tlast (AUC lected in K2EDTA tubes. The samples were calculated by the linear-logarithmic trapezoi- processed to plasma (centrifugation at 2000 dal method up to the last time point with a × g, 10 minutes, 4 °C) and subsequently fro- quantifiable concentration) and Cmax (maxi- zen at < –20 °C until analysis. mum drug concentration measured). Second- Richter, Donath, Wedemeyer, et al. 474

ity of test vs. reference was assessed by the Table 1. Demographic and anthropometric data of randomized subjects (full-analysis set, N = 34). ratios of geometric means (adjusted, equivalent to the Least Squares Mean) of AUC0–tlast, Arithmetic Median (range) mean (SD) AUC0–∞, and Cmax. Bioequivalence was con- Age (years) 32 (9) 32 (19 – 55) cluded, if the parametric 90% confidence Height (m) 1.73 (0.09) 1.75 (1.50 – 1.89) interval (CI) calculated for AUC0–tlast and Weight (kg) 74.1 (11.8) 78.5 (51.3 – 98.4) Cmax did not exceed the limits of 80.00% BMI (kg/m2) 24.5 (2.9) 24.5 (18.7 – 29.9) and 125.00%. This decision procedure cor- responds to two one-sided tests with an error BMI = body-mass index; SD = standard deviation. probability α = 0.05 each. Bioequivalence of the two products with respect to AUC0–∞ was assessed analogously in a descriptive manner.

Results Study participants

Of 44 enrolled subjects, 34 (17 female and 17 male) subjects, 19 to 55 years of age, were randomized (full-analysis set). The baseline characteristics are depicted in Table 1. One subject dropped out in period II after having completed all planned treatments (reason: withdrawal of consent not related to treatments administered). Thus, this subject remained in the pharmacokinetic evaluation (per-protocol set). Another subject dropped out due to a serious AE not related to the drug product in period I (see safety and tolerability) and was thus exclu ded from the per-protocol set (N = 33). There were no major protocol deviations such as incorrect inclusion, treatment, or dosing.

Figure 1. Arithmetic mean plasma concentrations of pridinol after single oral administration of test and reference in 33 healthy subjects (A: linear Pharmacokinetics scale, B: semilogarithmic scale). Shown are means and bioequivalence ± standard deviation. The mean plasma concentration-time ary pharmacokinetic parameters included profiles of pridinol after fasted oral admin- AUC0–∞ (AUC extrapolated to infinity), istration of test and reference show a highly AUCexpol% (extrapolated area% calculated similar and nearly superimposable course as Clast/λ × 100 / AUC0–∞; Clast = last quan- with a steep increase without a lag-time and tifiable concentration, λ = apparent terminal a maximum (= Cmax) at ~ 1 hour post dos- elimination rate constant determined by log- ing (Figure 1). The Cmax is followed by a linear regression), tmax (time from dosing to fast initial decrease until 6 hours post dose Cmax), and T1/2 (apparent terminal half-life). to a mean level of ~ 7 ng/mL. Thereafter, the Analyses of variances (ANOVA) were profiles switch to a slower elimination phase performed as pairwise comparisons of test until the end of the observed time period of vs. reference for ln-transformed values of 72 hours to mean values of ~ 0.5 ng/mL. The AUC0–tlast, AUC0–∞, and Cmax including the individual curves (Figure 2) show a quite factors formulation, period, sequence, and similar plasma concentration course for all subject(sequence). The relative bioavailabil- subjects. Pharmacokinetics of oral pridinol 475

Table 2. Descriptive statistics of pharmacokinetic parameters of pridinol (per-protocol set, N = 33).

AUC0–tlast (h×ng/mL) AUC0–∞ (h×ng/mL) AUCexpol% (%) Cmax (ng/mL) tmax (h) T1/2 (h) Test Ref Test Ref Test Ref Test Ref Test Ref Test Ref Mean 207.71 204.51 226.72 221.83 6.07 6.04 30.71 28.76 1.00 0.90 19.14 18.85 (SD) (100.42) (93.72) (128.78) (112.90) (5.08) (4.67) (9.34) (8.36) (0.36) (0.27) (5.97) (5.45) Median 189.98 182.92 197.11 191.77 5.04 5.04 31.04 27.45 1.00 0.77 18.00 18.21 (range) (49.68 (42.45 (50.77 (43.20 (0.91 (0.84 (10.64 (10.09 (0.50 (0.52 (9.37 (8.97 – 530.28) – 449.19) – 682.66) – 541.91) – 22.32) – 20.51) – 55.94) – 47.10) – 2.00) – 2.02) – 34.58) – 32.61) Geom. 187.93 183.51 200.38 195.54 4.39 4.47 29.27 27.44 0.95 0.87 18.30 18.11 mean (48.16) (52.36) (52.93) (56.48) (100.69) (98.21) (33.47) (33.54) (31.39) (24.61) (31.13) (29.44) (CV%)

AUC0–tlast = area under the curve from first to last assessment; AUC0–∞ = AUC extrapolated to infinity; AUCexpol% = extrapolated AUC%; Cmax = maximum plasma concentration; CV = coefficient of variation; SD = standard deviation;max t = time from dosing to Cmax; T1/2 = apparent terminal half-life.

rence. Likewise, the extent of bioavailability, represented by geometric mean AUC0–tlast, was nearly identical for test (187.93 h×ng/ mL, CV: 48.16%) and reference (183.51 h×ng/mL, CV: 52.36%). In 1 subject, the extrapolated area (AUCexpol%) slightly exceed- ed 20% (22.32% after test, 20.51% after reference). The subject remained in the analysis population since blood sampling over 72 hours is considered sufficient in the sense of a truncated area approach for drugs with a long T1/2 [4]. In all other cases, AUCexpol% was well below 20%. The mean time points of maximum exposure (tmax) were comparable for test (1.00 hour post dosing) and refe rence (0.90 hours post dosing). In all cases, tmax was observed after the first sampling time point. The calculated elimination half- lives (T1/2) ranged from 8.97 hours to 34.85 hours with comparable mean values for test (19.14 hours) and reference (18.85 hours). The point estimates of adjusted geometric means and the affiliated CIs for comparison of test and reference are shown in Table 3. CVANOVA were low for all analyzed para meters (15.42 – 18.30%). The point estimates for both primary parameters (AUC0–tlast and Cmax) were within the acceptance range of Figure 2. Overlay of individual plasma concentra- 80.00 – 125.00% suggested by the current tions of pridinol after single oral administration of A) guidelines, thus demonstrating bioequiva- test (Myoson direct) and B) reference (Lyseen) in lence between the two products. 33 healthy subjects.

The pharmacokinetic parameters calcu- Safety and tolerability lated from these profiles are listed in Table 2. The maximum exposure, represented by geo- No clinically relevant changes in vital metric mean Cmax, was quite similar for both signs and laboratory parameters were ob- products with 29.27 ng/mL (CV: 33.47%) for served between screening and end-of-study test and 27.44 ng/mL (CV: 33.54%) for refe examination. The AEs are summarized in Richter, Donath, Wedemeyer, et al. 476

Except for 1 AE (subject referred Table 3. Point estimates and confidence intervals of the ratio of adjusted geometric means of the primary and a selected secondary pharmacokinetic pa- to physician due to increased level of rameter (per-protocol set, N = 33). γ-glutamyltransferase), all AEs were re-

90% confidence interval solved at the end of the trial.

Parameter Point estimate (%) Lower limit (%) Upper limit (%) CVANOVA (%)

AUC0–tlast 102.54 96.19 109.32 15.42 Cmax 106.79 99.00 115.20 18.30 Discussion AUC0–∞ 102.60 96.20 109.43 15.52 The present clinical trial was conduc ANOVA = analysis of variance; AUC0–tlast = area under the curve from first to ted to assess the bioequivalence of the oral last assessment; AUC0–∞ = AUC extrapolated to infinity; Cmax = maximum plasma concentration; CV = coefficient of variation. immediate-release products Myoson direct (test) and Lyseen (reference), both containing 4 mg pridinol mesylate. The results of this study were the basis for the relaunch Table 4. Adverse events after intake of drug products (full-analysis set, N = 34). of pridinol into the German market in 2017 (brand: Myopridin 3 mg tablets) [2]. N (n) Test Reference This is the first detailed report on the AE 13 (21) 20 (29) Related AE1 14 (17) 14 (18) pharmacokinetic properties of pridinol in hu- Serious AE 0 1 (1) mans. Both pridinol products showed a very Mild AE 10 (12) 12 (14) similar in-vivo performance as suggested by Moderate AE 5 (8) 12 (12) superimposable plasma concentration pro- Severe AE 1 (1) 3 (3) files and highly comparable pharmacokinetic AEs by SOC parameters. All maximum concentrations Nervous system disorders 12 (15) 16 (16) were recorded well after the first sampling Gastrointestinal disorders 1 (2) 5 (6) time point. Except for 1 subject, extrapo- General disorders and administration site conditions 2 (2) 1 (2) lated areas (AUC ) did not exceed 20% Injury, poisoning and procedural complications 0 2 (3) expol% of AUC values. In general, blood sam- Ear and labyrinth disorders 0 1 (1) 0–∞ Infections and infestations 1 (1) 0 pling over 72 hours as done in the present Investigations 0 1 (1) trial is considered sufficient in the sense of Musculoskeletal and connective tissue disorders 1 (1) 0 a truncated area approach for drugs with a long T1/2 [10]. Hence, characterization of the 1Possibly or probably related to drug product. AE = adverse event; N = number exposure in this trial was in line with the cur- of subjects; n = number of events; SOC = system organ class. rent guideline [10], and the pharmacokinetic results are considered reliable. The bioequivalence of the test and reference product was Table 4. After drug product intake, 23 of 34 demonstrated for both primary parameters subjects (67.7%) reported 50 AEs. Of these, (AUC0–tlast and Cmax) with point estimates 35 AEs (70.0%) were assessed as probably slightly above 100%. The CIs were com- or possibly related to the drug product. The pletely within the conventional acceptance most frequently reported AEs were headache range of 80 – 125%. (15 findings in 14 subjects) and dizziness (15 The detected broad range of elimination findings in 11 subjects), followed by diarrhea half-lives (8.97–34.85 hours) may at least be (4 findings in 3 subjects) and nausea (3 find- partly explained by intersubject differences ings in 3 subjects). The majority of AEs were in metabolizing enzymes CYP2C19 and CY- of mild (52%) or moderate (40%) intensity. P2B6 [internal data]. CYP2C19 is subject One subject reported dizziness of mode to genetic polymorphism with a prevalence rate intensity in period I after treatment with rate of poor metabolizers ranging between the reference drug. Since this AE required 3% in Europeans and 12 – 22% in Asians inpatient hospitalization for diagnostic mea- [11]. Likewise, pharmacokinetically relevant sures, it was assessed as serious. However, polymorphisms of CYP2B6 have been de- based on the medical history of the subject, scribed [12]. However, from the therapeutic the event was assessed as not related to the practice with pridinol for many years, no in- drug product. The AE was resolved at the fluence of this inter-subject variability can be end of the trial. deduced on the drug’s safety and efficacy. Pharmacokinetics of oral pridinol 477

With respect to safety, the type and in- Conflict of interest tensity of AEs observed in this study were in accordance with the safety profile of the AW, FD, MR, and RSW were employees drug substance as described in the summary of SocraTec R&D GmbH, a CRO acting as of product characteristics [2]. contractor of Strathmann GmbH & Co.KG, during conduct of the trial and preparation of the manuscript. AH and CP were employees Conclusion of Strathmann GmbH & Co.KG during conduct of the trial and preparation of the manu- This is the first detailed report on the script. pharmacokinetic characteristics of pridinol. The test product (new brand: Myopridin 3 mg tablets) was found to be bioequivalent References to the reference product Lyseen after single- dose, fasting, oral administration. The safety [1] Forth W, Henschler D, Rummel W, Starke K. [Allgemeine und spezielle Pharmakologie und and tolerability of both pridinol preparations Toxikologie]. 6th edition. Mannheim, Leipzig, were in accordance with the known AE pro- Wien, Zurich: BI‐Wissenschaftsverlag; 1992. file of the drug substance. [2] Pridinol. Myopridin® 3 mg tablets (Strathmann) summary of product characteristics, last updated Aug 2019 [German Fachinformation]. [3] Baclofen. Summary of product characteristics Acknowledgment (generic products), last updated April 2020 [Ger- man Fachinformation]. The drug products were provided by [4] Tizanidine. Summary of product characteristics (generic products), last updated Dec 2015 [Ger- the sponsor of the trial (Strathmann GmbH man Fachinformation]. & Co. KG, Hamburg, Germany). The phar- [5] Tolperisone. Summary of product characteristics maceutical quality (in-vitro dissolution and (generic products), last updated May 2020 [Ger- content) of the products was checked by man Fachinformation]. [6] Methocarbamol. Ortoton® (Recordati), summary Biokirch GmbH, Seevetal, Germany. Bio- of product characteristics, last updated June 2019 analytical analyses were performed by ACC [German Fachinformation]. GmbH Analytical Clinical Concepts, Leider- [7] Fatoye F, Gebrye T, Odeyemi I. Real-world inci- sbach, Germany. J. Walstab (SocraTec R&D dence and prevalence of low back pain using rou- tinely collected data. Rheumatol Int. 2019; 39: GmbH, Erfurt, Germany) provided medical 619-626. writing assistance, supported by Strathmann [8] Stock B, Spiteller G. [Metabolism of antiparkin- GmbH & Co. KG. son drugs. An example of competitive hydroxyl- ation]. Arzneimittelforschung. 1979; 29: 610-615. [9] EMA. Guideline on bioanalytical method validation. EMEA/CHMP/EWP/192217/2009 Rev.1 Authors’ contribution Corr. 2**. 2011. [10] EMA. Guideline on the investigation of bioequiv- FD, RSW, AW, AH and CP contributed alence. CPMP/EWP/QWP/1401/98 Rev. 1 Corr.**. 2010. to conception and design of the study. MR, [11] Bertilsson L. Geographical/interracial differences FD, AD contributed to acquisition of data. in polymorphic drug oxidation. Current state of MR, FD, RSW, AW contributed to analysis knowledge of cytochromes P450 (CYP) 2D6 and and interpretation of data. All authors revised 2C19. Clin Pharmacokinet. 1995; 29: 192-209. [12] Ramli FF. Pharmacogenomics biomarkers for the article and approved the final version for personalized methadone maintenance treatment: submission. The authors had complete ac- The mechanism and its potential use. Bosnian cess to the data that support this publication. Journal of Basic Medical Sciences. 2020. https:// They directed and are fully responsible for www.bjbms.org/ojs/index.php/bjbms/article/ view/4897. all content and editorial decisions.

Funding The clinical trial and the generation of the manuscript were funded by Strathmann GmbH & Co KG, Hamburg, Germany.