Gilles-Jacques Riviere

Multiple-Dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects

FTY720 is a sphingosine‐1‐phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple‐dose FTY720. In this randomized, double‐blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month‐long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory Emax model. First‐dose exposure was consistent with dose proportionality between the low‐ and high‐dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for Cmax (5.0 ± 1.0 vs. 18.2 ± 4.1 ng/mL) and for AUC (109 ± 24 vs. 399 ±85 ng•h/ mL). Washout pharmacokinetics after the last dose indicated an elimination half‐life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 ± 0.1 × 109/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 ±0.1 ×109/L. Descriptive exposure‐response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end‐of‐study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low‐ and high‐dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose‐proportionality after both single‐ and multiple‐dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure‐response modeling provided evidence that 5 mg/day FTY720 resulted in a near‐maximal dynamic effect of this drug on lymphocytes.

Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus.

BackgroundVildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus.ObjectivesTo assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10mg, 25mg and l00mg twice daily following oral administration in patients with type 2 diabetes.MethodsThirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10mg, 25mg and l00mg as well as placebo twice daily for 28 days.ResultsVildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (>90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p < 0.001] and glucose-dependent insulinotropic peptide (GIP) [p < 0.001] were increased whereas postprandial glucagon was significantly reduced at the 25mg (p = 0.006) and l00mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25mg dosing regimen and by 2.5 mmol/L with the lOOmg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated.ConclusionVildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

Imatinib does not induce cardiotoxicity at clinically relevant concentrations in preclinical studies

Cytotoxic concentrations of imatinib mesylate (10-50 microM) were required to trigger markers of apoptosis and endoplasmic reticulum stress response in neonatal rat ventricular myocytes and fibroblasts, with no significant differences observed between c-Abl silenced and nonsilenced cells. In mice, oral or intraperitoneal imatinib treatment did not induce cardiovascular pathology or heart failure. In rats, high doses of oral imatinib did result in some cardiac hypertrophy. Multi-organ toxicities may have increased the cardiac workload and contributed to the cardiac hypertrophy observed in rats only. These data suggest that imatinib is not cardiotoxic at clinically relevant concentrations (5 microM).

Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Imatinib, a tyrosine kinase inhibitor, exhibits a competitive inhibition on the CYP450 2D6 isozyme with a K(i) value of 7.5 microm. However, the clinical significance of the inhibition and its relevance to 2D6 polymorphisms have not been evaluated. The pharmacokinetics of imatinib have been well studied in Caucasians, but not in a Chinese population. Metoprolol, a CYP2D6 substrate, has different clearances among patients with different CYP2D6 genotypes. It is often used as a CYP2D6 probe substrate for clinical drug-drug interaction studies. WHAT THIS STUDY ADDS Co-administration of imatinib at 400 mg twice daily increased the plasma AUC of metoprolol by approximately 23% in 20 Chinese patients with chronic myeloid leukaemia (CML), about 17% increase in CYP2D6 intermediate metabolizers (IMs) (n = 6), 24% in extensive metabolizers (EMs) (n = 13), and 28% for the subject with unknown 2D6 status (n = 1) suggesting that imatinib has a weak to moderate inhibition on CYP2D6 in vivo. * The clearance of imatinib in Chinese patients with CML showed no difference between CYP2D6 IMs and EMs, and no major difference from Caucasian patients with CML based on data reported in the literature. AIMS To investigate the effect of imatinib on the pharmacokinetics of a CYP2D6 substrate, metoprolol, in patients with chronic myeloid leukaemia (CML). The pharmacokinetics of imatinib were also studied in these patients. METHODS Patients (n = 20) received a single oral dose of metoprolol 100 mg on day 1 after an overnight fast. On days 2-10, imatinib 400 mg was administered twice daily. On day 8, another 100 mg dose of metoprolol was administered 1 h after the morning dose of imatinib 400 mg. Blood samples for metoprolol and alpha-hydroxymetoprolol measurement were taken on study days 1 and 8, and on day 8 for imatinib. RESULTS Of the 20 patients enrolled, six patients (30%) were CYP2D6 intermediate metabolizers (IMs), 13 (65%) extensive metabolizers (EMs), and the CYP2D6 status in one patient was unknown. In the presence of 400 mg twice daily imatinib, the mean metoprolol AUC was increased by 17% in IMs (from 1190 to 1390 ng ml(-1) h), and 24% in EMs (from 660 to 818 ng ml(-1) h). Patients classified as CYP2D6 IMs had an approximately 1.8-fold higher plasma metoprolol exposure than those classified as EMs. The oral clearance of imatinib was 11.0 +/- 2.0 l h(-1) and 11.8 +/- 4.1 l h(-1) for CYP2D6 IMs and EMs, respectively. CONCLUSIONS Co-administration of a high dose of imatinib resulted in a small or moderate increase in metoprolol plasma exposure in all patients regardless of CYP2D6 status. The clearance of imatinib showed no difference between CYP2D6 IMs and EMs.

Evaluation of Pharmacokinetic Interactions Between Vildagliptin and Digoxin in Healthy Volunteers

Vildagliptin is a novel antidiabetic agent that is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV, the enzyme responsible for degradation of the incretin hormones. This open‐label, randomized, 3‐period crossover study investigated the potential for pharmacokinetic interactions in 18 healthy subjects during coadministration of vildagliptin and digoxin. Subjects were randomized to receive each of 3 treatments: vildagliptin 100 mg qd, digoxin (0.5 mg, then 0.25 mg qd on days 2–7), and the combination vildagliptin/digoxin for 7 days. Coadministration of digoxin with vildagliptin had no effect on exposure to vildagliptin (geometric mean ratios [90% confidence interval]: AUC0‐24h, 0.99 [0.95–1.03]; Cmax, 0.95 [0.85–1.06]) or to digoxin (AUC0‐24h, 1.02 [0.94–1.12]; Cmax, 1.08 [0.97–1.20]). In addition, no changes in tmax, t1/2, and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.

Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

ABSTRACT Objective: Vildagliptin is a potent and selective dipeptidyl peptidase‑IV (DPP‑4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100 mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg oral dose of warfarin sodium. Research design and methods: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects. Results: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S‑warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S‑warfarin maximum plasma concentration (Cmax) were also within the equivalence range 0.80–1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PTmax, 1.00 [90% CI 0.97, 1.04]; AUCPT, 0.99 [0.97, 1.01]) and international normalized ratios (INRmax, 1.01 [0.98, 1.05]; AUCINR, 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80–1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication. Conclusions: Co-administration of warfarin with vildagliptin did not alter the pharmacokinetics and pharmacodynamics of R- or S‑warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.

The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects

AIMS The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod. METHODS In this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110-120 beats min(-1)) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose. Continuous telemetry measurements were made for 24 h after each fingolimod dose. RESULTS Fingolimod administration alone yielded a heart rate nadir of 51 +/- 5 beats min(-1) at a median 4 h postdose with heart rate remaining depressed at 51-64 beats min(-1) over the rest of the day. Concurrent administration of fingolimod and atropine yielded a nadir of 66 +/- 6 beats min(-1) resulting in an atropine: placebo ratio (90% confidence interval) of 1.30 (1.22, 1.36). When atropine was administered at the time of the nadir, it was able to reverse the negative chronotropic effect of fingolimod from a heart rate of 56 +/- 9 beats min(-1) (placebo) to 64 +/- 8 beats min(-1) (atropine) resulting in an atropine: placebo ratio of 1.15 (1.04, 1.26). Atropine had no influence on the pharmacokinetics of fingolimod. CONCLUSIONS Atropine administered concurrently with fingolimod prevented the heart rate nadir that typically occurs 4 h postdose. Atropine administered at the time of the heart rate nadir was able to reverse the negative chronotropic effect of fingolimod.

Fingolimod (FTY720) in Severe Hepatic Impairment: Pharmacokinetics and Relationship to Markers of Liver Function

The authors assessed the impact of severe hepatic impairment on the disposition of fingolimod—a sphingosine‐1‐phosphate receptor immunomodulator primarily metabolized by CYP4F2—in 6 patients and 6 matched healthy controls who received a single 5‐mg oral dose. Compared with healthy controls, severe hepatic‐impaired subjects had a doubled area under the concentration time curve (AUC) and 50% prolonged elimination half‐life but a similar peak blood concentration. When these data were combined with those from a previous study in mild and moderate hepatic‐impaired subjects, there were significant positive correlations between fingolimod AUC versus bilirubin (r = 0.683) and prothrombin time (r = 0.777) and a significant negative correlation versus albumin (r = 0.578), confirming the importance of liver function for fingolimod clearance. For patients with severe hepatic impairment (Child‐Pugh class C), a standard first dose of fingolimod could be given followed by a maintenance dose that is reduced by half from the normal maintenance dose.

Omalizumab Protects against Allergen- Induced Bronchoconstriction in Allergic (Immunoglobulin E-Mediated) Asthma

Background: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. Methods: Asthmatic adults (18–65 years; body weight 40–150 kg) were divided into groups according to screening IgE (group 1: 30–300 IU/ml; group 2: 700–2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12–14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FENO) was an exploratory endpoint. Results: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6–16. Omalizumab completely suppressed FENO increases after ABP in both groups. Conclusions: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

Ketoconazole Increases Fingolimod Blood Levels in a Drug Interaction via CYP4F2 Inhibition

The sphingosine‐1‐phosphate receptor modulator fingolimod is predominantly hydroxylated by cytochrome CYP4F2. In vitro experiments showed that ketoconazole significantly inhibited the oxidative metabolism of fingolimod by human liver microsomes and by recombinant CYP4F2. The authors used ketoconazole as a putative CYP4F2 inhibitor to quantify its influence on fingolimod pharmacokinetics in healthy subjects. In a 2‐period, single‐sequence, crossover study, 22 healthy subjects received a single 5‐mg dose of fingolimod in period 1. In period 2, subjects received ketoconazole 200 mg twice daily for 9 days and a single 5‐mg dose of fingolimod coadministered on the 4th day of ketoconazole treatment. Ketoconazole did not affect fingolimod tmax or half‐life, but there was a weak average increase in Cmax of 1.22‐fold (90% confidence interval, 1.15–1.30). The AUC over the 5 days of ketoconazole coadministration increased 1.40‐fold (1.31–1.50), and the full AUC to infinity increased 1.71‐fold (1.53–1.91). The AUC of the active metabolite fingolimod‐phosphate was increased to a similar extent by 1.67‐fold (1.50–1.85). Ketoconazole predose plasma levels were not altered by fingolimod. The magnitude of this interaction suggests that a proactive dose reduction of fingolimod is not necessary when adding ketoconazole to a fingolimod regimen. The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring.