Johan Wemer

CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences.

AbstractObjective: We examined a large database containing results on CYP2D6 and CYP2C19 activity of 4301 Dutch volunteers phenotyped in the context of various clinical pharmacology studies. Methods: The subjects were given 22 mg dextromethorphan, 100 mg mephenytoin and 200 mg caffeine. For CYP2D6, the dextromethorphan/dextrorphan metabolic ratios in urine samples taken for a subsequent 8 h were used. Dextromethorphan and dextrorphan were quantified by reversed-phase high performance liquid chromatography. For CYP2C19 similarly obtained (R)-mephenytoin and (S)-mephenytoin ratios were used. (S)-mephenytoin and (R)-mephenytoin were analysed and quantified by enantioselective capillary gas chromatography. In addition, CYP2C19 poor metabolizer (PM) subjects were reanalysed after acidic pre-treatment of urine samples to confirm the PM status. Results: The investigated population mainly comprised Caucasian (98.9%) males (68%). The age ranged from 18 to 82 years. For CYP2D6, it was found that 8.0% of the subjects were PMs. The average metabolic ratio was 0.014 (0.033) for subjects who showed extensive metabolizing activity (EM) and 5.4 (7.6) for PM subjects. For CYP2C19, it was found that 1.8% of the subjects were PMs. The metabolic ratio was 0.162 (0.124) for EM subjects and 1.076 (0.040) for PM subjects. Within the EM group the metabolic ratio in females was significantly lower for CYP2D6 (−20%) and significantly higher for CYP2C19 (+40%) compared with males. For PMs there was no such difference for CYP2D6 (P = 0.79) or CYP2C19 (P = 0.20). Oral contraceptive (OC) use significantly decreased the CYP2C19 activity by 68% for mephenytoin as compared to non-OC using females. Conclusions: For CYP2D6, the PM incidence (8.0%) is in accordance with literature data. The CYP2C19, PM incidence (1.8%) is low compared to reports from other European countries. For mephenytoin, the acidification procedure has been shown to be very important for the confirmation of CYP2C19 PMs. In EM females compared to EM males, CYP2D6 activity is increased and CYP2C19 activity is reduced. For CYP2C19 in particular this reduction is substantial and most pronounced in the age range from 18 to 40 years. For CYP2C19, the reduced activity is associated with the use of oral contraceptives.

Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue

Solulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6-30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15-30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

BACKGROUND Fingolimod has a novel mechanism of action in multiple sclerosis, being a first-in-class sphingosine 1-phosphate receptor modulator. Because of a potential risk of fetal toxicity based on animal studies, women of childbearing potential are advised to take effective contraceptive measures during and for 2 months after stopping fingolimod therapy. To assess whether the efficacy of a combined oral contraceptive (OC) could be compromised during fingolimod therapy, a steady-state, drug-drug interaction study of fingolimod with ethinylestradiol/levonorgestrel was performed in healthy female volunteers. OBJECTIVE To assess the interaction between fingolimod 0.5 mg once daily and ethinylestradiol 30 μg/ levonorgestrel 150 μg once daily at a steady state. METHODS 31 healthy women received the combined OC only on Days 1 - 14, followed by OC plus fingolimod on Days 15 - 28. RESULTS In the presence of fingolimod, ethinylestradiol pharmacokinetics were unchanged, and levonorgestrel maximum plasma concentration at steady state and area under the concentration-time curve during a dosing interval increased by factors of 1.10 (90% CI 1.05 - 1.16) and 1.22 (90% CI 1.18 - 1.27), respectively. CONCLUSIONS Fingolimod therapy does not alter the pharmacokinetics of the combined OC ethinylestradiol/ levonorgestrel to a clinically significant degree. Ethinylestradiol/levonorgestrel does not alter the pharmacokinetics of fingolimod. Women receiving fingolimod therapy are able to use a combined OC as a means of effective birth control.

Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects.

ABSTRACT Objective: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cuss) exposure range of 50-300 μmol/L in healthy young and elderly subjects. Research design and methods: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8‐h and 72‐h intravenous infusions of NXY‐059 in healthy young (20–45 years) and elderly (55–75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8‐h and 72‐h intravenous infusions of NXY‐059 in these subjects, using blood and urine samples taken during and after NXY‐059 infusion as well as the doses administered. Results: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY‐059 and placebo subjects were similar, although headache was more common in the NXY‐059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8‐h and 72‐h infusions was observed, and clearance did not change with dose. Conclusions: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8‐h and 72‐h infusions of NXY‐059 at doses resulting in an average Cuss in the 52–317 µmol/L range.

NXY-059 Does Not Affect Bleeding Time in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, 3-Period Crossover Phase I Study

NXY‐059 is a novel free radical–trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. It is the first neuroprotectant to demonstrate a reduction in global disability in a phase III clinical trial, as measured by the modified Rankin Scale. Any effect of NXY‐059 on hemostasis may be important when treating stroke patients. This phase I randomized, double‐blind, placebo‐controlled, 3‐period crossover study compared the effect of NXY‐059, desmopressin, and placebo on bleeding time, platelet aggregation, and adhesion in 30 healthy volunteers. NXY‐059 did not prolong bleeding time compared with placebo: mean (SD) time for NXY‐059, 369.5 seconds (125.0 seconds) versus placebo, 369.1 seconds (136.0 seconds). There were no significant effects on platelet aggregation or adhesion. At a mean unbound plasma concentration (Cuss) of 335 μmol/L, NXY‐059 was well tolerated, with no major safety concerns identified. In conclusion, NXY‐059 does not appear to affect primary hemostasis.

Active Renal Secretion of NXY-059, a Novel Neuroprotectant, Is Mediated via an Organic Acid Transporter

N (disufenton sodium) is a novel, freeradical–trapping neuroprotectant, which, until recently, was in clinical development for the treatment of acute ischemic stroke based on effects seen in experimental animal models. Phase 1 studies in healthy subjects receiving intravenous (iv) infusions of NXY-059 demonstrated that it is mainly eliminated unchanged by renal excretion. Furthermore, these data indicated that passive tubular reabsorption of NXY-059 does not occur because renal clearance (CLR) was insensitive to changes in pH and urine flow rate. Analysis of CLR data indicated that approximately 30% of renal elimination is a result of active secretion in the kidney. A study undertaken in subjects with renal impairment indicated that plasma clearance of NXY-059 correlated highly to kidney function measured as glomerular filtration rate (GFR). The study concluded that the contribution of nonrenal clearance to the overall clearance of NXY-059 was negligible. The purpose of this study was to further characterize the active renal excretion of NXY-059. NXY-059 is a disulfonate salt with both of its pKa values less than 2. At physiological pH of the blood, most of NXY-059 will exist in the unprotonated form and will be ionized as an acid. Therefore, NXY-059 would be a likely candidate for secretion by an active (carrier-mediated and energy-dependent) organic acid transport system. However, because the N-oxide moiety of NXY-059 also carries a partial positive charge, the possibility also exists that NXY-059 could be secreted by an active transporter for organic bases. Probenecid and cimetidine were used as model inhibitors in this study to further characterize the renal excretory mechanisms of NXY-059 because these drugs are known to be inhibitors of renal systems that transport organic acids and bases, respectively. In addition, inulin was used for monitoring GFR during the study.