Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism.

PURPOSE: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. METHODS: Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. RESULTS: Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. CONCLUSIONS: The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.

Similar rivastigmine pharmacokinetics and pharmacodynamics in Japanese and white healthy participants following the application of novel rivastigmine patch.

The pharmacokinetics and pharmacodynamics of rivastigmine were compared in Japanese and white healthy participants who were given ascending single doses of the novel rivastigmine transdermal patch. Rivastigmine patch strengths were 4.6 mg/24 h (5 cm2, 9 mg rivastigmine loaded dose), 9.5 mg/24 h (10 cm2, 18 mg), and 13.3 mg/24 h (15 cm2, 27 mg) (per label) or 7.0 mg/24 h (7.5 cm2, 13.5 mg) as a fall-back dose. No relevant ethnic differences in the noncompartmental pharmacokinetics (parent and metabolite NAP226-90) and pharmacodynamics (plasma BuChE activity) of the rivastigmine patch were observed between Japanese and whites. However, drug exposure was slightly higher and inhibition of BuChE slightly more pronounced in Japanese participants than in whites, which was attributed to the lower body weight (ca. 11% less on average) of Japanese participants. Treatments were similarly well tolerated in both ethnic groups. In conclusion, no relevant ethnic differences in the intrinsic disposition or effects of rivastigmine delivered via transdermal route are expected between Japanese and white patients. The possible effect of body weight on drug exposure suggests that special attention should be paid to patients with very low body weight during up-titration.

Cannabinoid receptor agonist 13, a novel cannabinoid agonist: first in human pharmacokinetics and safety.

Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB(1) and CB(2) receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n = 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n = 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (C(max)) ranged from 7.8 to 467.6 ng/ml (1-80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1-80 mg). Time to reach C(max) (t(max)) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the C(max) and the area under the concentration-time curve, AUC(0 - tz). The apparent elimination half-life (t(1/2)) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40- and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1-80 mg). Food intake increased CRA13 C(max) and AUC(0 - tz) by approximately 2-fold, whereas t(max) was unaffected.

Pharmacokinetics of licarbazepine in healthy volunteers: single and multiple oral doses and effect of food.

Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics.

Rivastigmine exposure provided by a transdermal patch versus capsules.

OBJECTIVES: The rivastigmine transdermal patch is the first transdermal treatment for Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The objective of this study was to evaluate the pharmacokinetics of rivastigmine following transdermal delivery by a patch versus oral delivery with conventional capsules in a population of AD patients. METHODS: Both non-compartmental and compartmental analyses were performed on the same database showing relatively large inter-patient variations in pharmacokinetic parameters (up to 73% for the capsule group). The compartmental analysis provided model-based predictions of pharmacokinetic parameters, with the aim of comparing the two modes of administration when adjusting for confounding factors such as patient body weight and gender. RESULTS: According to both non-compartmental and compartmental analyses, the patch provided significantly lower peak rivastigmine plasma concentrations (C(max)) and slower times to C(max) (t(max)), compared with capsules. However, drug exposure (area under the curve; AUC) was not significantly different between the 4.6 mg/24 hour (5 cm(2)) patch and 3 mg BID (6 mg/day) capsule doses, or between the 9.5 mg/24 hour (10 cm(2)) patch and 6 mg BID (12 mg/day) capsule doses, according to both analyses. This suggests comparable exposure from these two rivastigmine delivery systems. CONCLUSION: The analyses were consistent with previous reports of a markedly less fluctuating, more continuous drug delivery with the rivastigmine patch. This characteristic delivery profile is associated with similar efficacy yet improved tolerability, compared with capsules.

Integrated pharmacokinetics and pharmacodynamics in drug development.

Drug development is a complex, lengthy and expensive process. Pharmaceutical companies and regulatory authorities have recognised that the drug development process needs optimisation for efficiency in view of the return on investments. Pharmacokinetics and pharmacodynamics are the two main principles determining the relationship between dose and response. This article provides an update on integrated approaches towards drug development by linking pharmacokinetics, pharmacodynamics and disease aspects into mathematical models. Gradually, a transition is taking place from a rather empirical approach towards a modelling- and simulation-based approach to drug development. The main learning phases should be phases 0, I and II, whereas phase III studies should merely have a confirmatory purpose. In model-based drug development, mechanism-based mathematical models, which are iteratively refined along the path of development, incorporate the accumulating knowledge of the investigational drug, the disease and their mutual interference in different subsets of the target population. These models facilitate the design of the next study and improve the probability of achieving the projected efficacy and safety endpoints. In this article, several theoretical and practical aspects of an integrated approach towards drug development are discussed, together with some case studies from different therapeutic areas illustrating the application of pharmacokinetic/pharmacodynamic disease models at different stages of drug development.

Pharmacokinetic rationale for the rivastigmine patch.

The dual cholinesterase inhibitor rivastigmine is approved in capsule form in many countries for the symptomatic treatment of dementia associated with Alzheimer disease (AD) and Parkinson disease (PD). All orally administered cholinesterase inhibitors are associated with central cholinergic gastrointestinal side effects, particularly during the titration phase, which are believed to be caused by a rapid increase in brain acetylcholine levels after effective inhibition of the target enzymes. A recently developed rivastigmine transdermal patch may have the potential to reduce such side effects. Pharmacokinetic studies have shown that transdermal administration of rivastigmine prolongs t(max), lowers C(max), and reduces fluctuations in plasma concentration. The 10-cm(2) rivastigmine patch provides comparable exposure (area under the curve, AUC) to the highest capsule dose (6-mg BID) and may be the target maintenance dose for most patients, delivering optimal rivastigmine exposure to produce a therapeutic effect. The potential of a patch to improve the tolerability of rivastigmine (e.g., nausea and vomiting) while permitting similar exposure to the highest doses of capsules may, in turn, lead to improved efficacy and compliance.

Dose-proportional pharmacokinetics of d-threo-methylphenidate after a repeated-action release dosage form.

A bimodal extended-release formulation of d-methylphenidate (d-MPH) has been developed to enable fast onset of action and once-daily administration in patients with attention deficit hyperactivity disorder. The authors studied the dose proportionality of extended-release d-MPH pharmacokinetics. Twenty-five healthy adult volunteers received 5, 10, 20, 30, and 40 mg d-MPH in a crossover study with 7 days between doses. All doses were well tolerated. Dose proportionality was shown for all dose-dependent pharmacokinetic parameters. Geometric means (%gCV) for the first Cmax peak, Cmax0-4, were 3.25 (29.0%), 6.05 (27.1%), 12.6 (31.9%), 18.5 (31.9%), and 25.2 ng/mL (29.3%) for d-MPH 5, 10, 20, 30, and 40 mg, respectively. Geometric means (%gCV) for Cmax4-10 were 3.18 (27.5%), 5.84 (27.7%), 12.5 (31.7%), 17.7 (31.6%), and 23.6 ng/mL (29.0%), respectively. Geometric means for AUC(0-infinity) were 24.3 (30.7%), 45.9 (30.2%), 96.4 (35.5%), 144 (33.3%), and 195 ng x h/mL (30.9%), respectively. The pharmacokinetics of once-daily extended-release d-MPH are proportional to the dose.

Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects.

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open-label, parallel-group study, the pharmacokinetics of a single 12-mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h-tz), ng.h/ml: 14.6 +/- 8.5 vs. 14.3 +/- 7.1; Cmax, ng/ml: 4.6 +/- 2.3 vs. 5.1 +/- 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.

Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with promotile activity.

Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT(4) receptor partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who identify abdominal pain or discomfort and constipation as their predominant symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS. Tegaserod is rapidly absorbed following oral administration; peak plasma concentrations (C(max)) are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the C(max) by 20 to 40%. Systemic exposure to tegaserod is not significantly altered at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is approximately 98% bound to plasma proteins, primarily to alpha(1)-acid glycoprotein, and has a volume of distribution at steady-state of 368 +/- 223L. Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT(4) receptors and is devoid of promotile activity. The second is direct glucuronidation which leads to generation of three isomeric N-glucuronides. The plasma clearance of tegaserod is 77 +/- 15 L/h, with an estimated terminal half-life of 11 +/- 5 hours following intravenous administration. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine, primarily as M 29.0. The pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg given twice daily for 5 days, with no relevant accumulation. The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild to moderate hepatic or renal impairment. Tegaserod should not be used in patients with severe hepatic or renal impairment. No clinically relevant drug-drug interactions with tegaserod have been identified. In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP) 1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate), digoxin, warfarin and oral contraceptives have indicated no clinically relevant interactions and no requirement for dosage adjustment.

Tegaserod, a 5-hydroxytryptamine type 4 receptor partial agonist, is devoid of electrocardiographic effects.

OBJECTIVES: Certain GI prokinetic agents have been shown to affect cardiac repolarization, which may be associated with life-threatening arrhythmias. The selective 5-hydroxytryptamine type 4 receptor partial agonist tegaserod is a novel promotile agent developed for the treatment of functional motility disorders such as irritable bowel syndrome (IBS). The aim of the study was to investigate the cardiac safety profile of tegaserod through analysis of electrocardiographic data from clinical studies conducted in patients with IBS and a study conducted in healthy male subjects. METHODS: In three randomized, double blind, placebo-controlled, parallel group clinical studies, 2516 IBS patients with symptoms of abdominal pain and constipation received tegaserod 2 or 6 mg b.i.d. (n = 1679) or placebo (n = 837) for 12 wk. In an additional study, 36 healthy male subjects received iv. single doses of tegaserod (0.8 mg to 20 mg) or placebo. Standard 12-lead electrocardiograms were recorded at baseline and during treatment. Baseline values were compared with data collected during the treatment period. RESULTS: The proportion of patients with prolongation of the QTc interval was the same for placebo and tegaserod, as was the frequency of overall electrocardiographic abnormalities. No ventricular or supraventricular tachycardia was observed. Comparable electrocardiographic results were obtained during placebo and tegaserod treatment. In healthy volunteers, tegaserod at i.v. doses resulting in plasma concentrations up to 100 times those measured after therapeutic doses (6 mg b.i.d.) did not influence electrocardiographic parameters. CONCLUSIONS: Tegaserod is devoid of electrocardiographic effects and is not expected to adversely influence cardiac function. These data confirm preclinical findings.