An evaluation of human ADME and mass balance studies using regular or low doses of radiocarbon.

There has been increased interest in conducting human absorption, distribution, metabolism, and excretion (ADME) studies with low doses (up to 0.1 MBq) as opposed to regular doses (1.85-3.7 MBq) of radiocarbon (14 C). This is due to the fact that low-dose human ADME studies may be conducted without dosimetry calculations and will lead to lower human radiation exposure. Here, we sought to compare the outcomes of low-dose versus regular-dose human ADME studies in healthy volunteers. Forty oral human ADME studies conducted at PRA were surveyed, among which 12 were low-dose studies. The fraction of drug material absorbed was 67% ± 7% in the regular-dose studies (data for 13 studies) versus 39% ± 16% in the low-dose studies (data for 5 studies). The average total recovery of 14 C in excreta was 93% ± 5% for regular-dose studies, and 21 of 28 such studies showed recoveries more than 90%. For low-dose studies, average total recovery was 89% ± 9%, and 6 of 12 studies showed recoveries more than 90%. Metabolite profiling was successful in all cases reported (13 regular-dose studies and 5 low-dose studies). There was no obvious relationship between the total recoveries of 14 C in excreta and the proportion of 14 C excreted in feces, or between the total recoveries and the plasma elimination half-lives for parent or total 14 C, neither in the low-dose nor the regular-dose studies. A significant correlation was found between the fraction absorbed and the recovery in feces in the low-dose but not in the regular-dose studies, and no correlation was found between the fractions absorbed and the total recoveries in both types of studies. Low-dose studies were more often conducted on drugs that had a plasma elimination half-life of parent drug more than 100 hours (5 of 12 studies) than regular-dose studies (1 of 26 studies). We conclude that both low-dose as well as regular-dose human ADME studies provide adequate data to support decision making for further drug development.

Sotrastaurin and everolimus pharmacokinetics after single-dose coadministration.

INTRODUCTION: Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4. METHODS: This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment. RESULTS: Coadministration of everolimus decreased sotrastaurin C(max) from 638 +/- 295 to 539 +/- 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 - 1.00). Sotrastaurin total AUC was not altered by everolimus with values of 3660 +/- 1853 versus 3630 +/- 2006 ng*h/ml and a ratio of 1.00 (0.88 - 1.13). Sotrastaurin increased everolimus C(max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased everolimus total AUC from 114 +/- 50 to 137 +/- 56 ng*h/ml yielding a ratio of 1.20 (1.05 - 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels cannot be excluded. CONCLUSIONS: Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.

A Novel Method for Studying the Pharmacokinetics of [(14) C]Umeclidinium After Application to the Axilla or Palm of Healthy Male Subjects.

Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [(14) C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [(14) C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8-fold. Due to UMEC absorption-limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two-compartment population model with sequential zero and first-order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects.

Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers.

OBJECTIVE: A novel sulfonamide derivative, S-3304, was discovered as a potent matrix metalloproteinase (MMP) inhibitor. It is a more specific inhibitor to MMP-2 and MMP-9 (in vitro) than to MMP-1, and may therefore lack the musculoskeletal side effects seen with non-specific inhibitors. The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of S-3304 when administered as single and multiple oral doses to healthy male volunteers. MATERIALS AND METHODS: 48 male volunteers received single oral doses ranging from 10 - 800 mg S-3304 or placebo under fasting conditions. At the 200 mg dose level, effects of high-fat diets were studied in a crossover design. In the multiple dose design, 24 male subjects were administered 200 mg, 400 mg or 800 mg S-3304 or placebo b.i.d. after meals for 10 - 17 days. Studies were conducted in a randomized double-blind fashion. Safety assessment was conducted based on blood chemistry, hematology, urinalysis, electrocardiogram and physical examination. Pharmacokinetic parameters were determined for S-3304 and its metabolites. All subjects were enrolled in the studies after obtaining informed consent. RESULTS: Adverse events reported after single dose administration of S-3304 or placebo were all of mild severity. Adverse events reported in the multiple dose treatment with S-3304 or placebo were mostly of mild severity, except for two episodes of moderate headache and two episodes of moderate myalgia. Most commonly reported adverse events in the multiple treatments with S-3304 were headache and somnolence. No clinically significant changes were observed in the clinical laboratory tests, except for reversible elevation of alanine aminotransferase of one subject at 800 mg S-3304 b.i.d. In the single dose administration, Cmax and mean AUC0-infinity linearly increased up to 63,167 ng/ml and 311,960 ng x h/ml at the 800 mg dose level, respectively; tmax and t1/2 ranged from 2 - 3 hours and from 9.5 - 15.5 hours, respectively. High-fat diets reduced Cmax from 21,565 ng/ml to 14,095 ng/ml but did not alter AUC0-infinity. Hydroxylated metabolites were detected in plasma in concentrations less than 1% of S-3304. Less than 1% S-3304 was excreted in urine. The AUC of one dosing interval and Cmax did not change after multiple doses but t1/2 increased from 9.5 - 10.0 hours to 12.5 - 13.5 hours. The 6beta-hydroxycortisol/ cortisol ratio was not changed after multiple doses suggesting no effect on CYP3A4 activity. CONCLUSION: S-3304 demonstrated a good safety profile and good systemic exposure when administered orally up to 800 mg b.i.d. during 10 - 17 days. At the highest dose level of 800 mg b.i.d., it was free of rheumatoid arthritis-like symptoms.

Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects.

INTRODUCTION: Bosentan (Ro 47-0203) is a potent and mixed ETA-and ETB-receptor antagonist. Its activity has been studied in a variety of preclinical disease models. METHODS: Two double-blind placebo-controlled studies were performed to investigate the pharmacokinetics and pharmacodynamics of bosentan after single oral and intravenous doses in healthy volunteers; doses of 3, 10, 30, 100, 300, 600, 1200, and 2400 mg were given in a single ascending oral dose study, and doses of 10, 50, 250, 500, and 750 mg were given in a single ascending intravenous dose study (six subjects received active drug and two received placebo at each dose level). In an open-label crossover added to the second study, six subjects received a single oral dose of 600 mg and a single intravenous dose of 250 mg in randomized order. At regular intervals, blood pressure, pulse rate, and skin responses to intradermally injected endothelin-1 (ET-1) were recorded, and plasma levels of ET-1, proendothelin-1 (big ET-1), and ET-3, and drug and urinary levels of ET-1 and drug were determined. RESULTS: Systemic plasma clearance and volume of distribution decreased with increasing dose to limiting values of around 6 L/hr and 0.2 L/kg, respectively. The absolute bioavailability was 50% and appeared to decrease with doses above 600 mg. Plasma ET-1 increased maximally twofold (oral) and threefold (intravenous), and this increase was directly related to bosentan plasma concentrations according to an Emax model. Bosentan reversed the vasoconstrictor effect of ET-1 measured in the skin microcirculation. There was a tendency toward decreased blood pressure (approximately 5 mm Hg) and increased pulse rate (approximately 5 beats/min), neither was clearly dose dependent. Oral bosentan was well tolerated. Vomiting and local intolerability was observed at the higher intravenous doses. CONCLUSION: Bosentan is an orally bioavailable, well-tolerated, and active ET-1 antagonist with a low clearance and a moderate volume of distribution. Its intravenous use is limited because of local intolerability.

Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers.

The multiple-dose pharmacokinetics, safety, and tolerability of oral bosentan, a selective endothelin receptor antagonist, were investigated in healthy male volunteers. In study A, an ascending-dose, double-blind, placebo-controlled trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double-blind, placebo-controlled trial, 500 mg tablets of bosentan or placebo tablets were given once daily for 8 days with two additional single intravenous dose administrations of 250 mg bosentan 48 hours before the first and 24 hours after the last oral dose. The drug was very well tolerated. No effects on pulse rate, ECGs, or clinical laboratory tests were observed. Marginal effects on blood pressure were seen in subjects only when standing. The oral bioavailability of bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses above 500 mg did not lead to significant further increases in plasma levels of bosentan. From the first to the last day of the oral treatment phase, plasma concentrations of bosentan decreased by 30% to 40% due to a 2-fold increase in plasma clearance. Absorption and plasma protein binding did not change. The 24-hour urinary excretion of 6 beta-hydroxycortisol was increased in parallel by approximately 1.7-fold, indicating induction of cytochrome P450 3A isozymes. The two metabolites of bosentan reached plasma concentrations well below those of bosentan and will most likely not contribute to the pharmacological activity.

Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers.

The study was conducted in healthy male volunteers to evaluate the absorption, metabolic pattern, and mode of elimination of telmisartan, a nonpeptide angiotensin II receptor antagonist. [14C]telmisartan was administered orally in solution as a single 40 mg dose to 5 subjects. A further 5 subjects received short-term intravenous infusion of [14C]telmisartan 40 mg. Measurement of total 14C radioactivity in plasma showed that about 50% was absorbed following oral administration, with maximum plasma concentration observed after 0.5 to 1 hour. Absolute bioavailability was 43%. On average, 84% of total radioactivity in plasma reflected the parent compound. The remainder of total radioactivity could be ascribed to the glucuronide conjugate of telmisartan, which represented the only metabolite in man. About 99.5% of telmisartan was bound to plasma protein, mainly to albumin and alpha-1-acid glycoprotein. Telmisartan was reversibly distributed into erythrocytes. More than 90% of administered dose was excreted within 120 hours, and the excretion balance was complete 144 hours after dosing. Radioactivity was almost exclusively (> 98%) excreted via the feces; urinary excretion accounted for < 1% of the dose, irrespective of the route of administration. In the small fraction excreted into urine, the glucuronide conjugate of telmisartan was predominant. Although some telmisartan glucuronide was detected in plasma, only unchanged drug was identified in the feces. No changes in vital signs, electrocardiogram, or clinical laboratory tests were detected following telmisartan administration, and adverse events, predominantly unrelated to treatment and of mild intensity, were infrequent. One subject fainted and, on another occasion, reported faintness; these events were probably due to the antihypertensive action of the intravenous study medication.

Pharmacokinetics and pharmacodynamics of inhaled GLP-1 (MKC253): proof-of-concept studies in healthy normal volunteers and in patients with type 2 diabetes.

MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.

Troglitazone has no effect on red cell mass or other erythropoietic parameters.

OBJECTIVE: Troglitazone is a new anti-diabetic agent for the treatment of type 2 diabetes. In placebo-controlled trials troglitazone improves glycaemic control, reduces hyperinsulinaemia and has beneficial effects on blood lipids. However, minor, reversible reductions in erythrocyte count, haemoglobin and haematocrit with no associated clinical symptoms have been observed in some troglitazone-treated patients. The primary objective of the present study was to determine if these changes could be explained by a decrease in red cell mass or change in plasma volume. METHODS: Twenty-four healthy males were randomized in a double-blind manner to troglitazone (200 or 600 mg per day) or placebo for 6 weeks. Blood samples for the measurement of red cell mass and plasma volume were obtained in the 2 weeks prior to treatment and after 6 weeks of treatment. Reticulocyte and erythrocyte counts, haemoglobin and haematocrit were also measured. RESULTS: At the end of the treatment period there were no statistically significant changes in red cell mass. Similarly there were no changes in reticulocyte count, erythropoietin or soluble transferrin receptors. These data indicate that troglitazone does not affect erythropoiesis. In addition, troglitazone was not associated with increased red blood cell destruction or haemolysis. There was a trend towards increased plasma volume in the troglitazone groups: increases of 2.5 ml x kg(-1) (5.7% increase) in the troglitazone 200 mg group and 3.4 ml x kg(-1) (7.8% increase) in the troglitazone 600 mg group were observed compared with placebo. CONCLUSION: These data suggest that dilutional effects related to a modest increase in plasma volume may explain the haematological changes seen in other clinical trials with high doses of troglitazone, although this study has shown that the changes in plasma volume are not statistically significant.

Tizanidine versus baclofen in the treatment of spasticity in multiple sclerosis patients.

Sixteen patients suffering from spasticity due to multiple sclerosis were treated with baclofen and tizanidine in a partially blind cross-over study. No significant difference in efficacy was found. The most striking difference was seen in the side-effects: baclofen frequently caused more or less severe muscle weakness and even falling during walking and standing. Treatment with tizanidine produced an apparent improvement of mobility in some patients suffering from moderate or marked paresis associated with a marked spasticity of their legs. Isometric muscle strength did not show any significant changes during either treatment. The different impact of baclofen and tizanidine on mobility and weight support seems to be related to their different site of action in spasticity.