Exposure-response modeling and clinical trial simulation of the effect of tolterodine on QT intervals in healthy volunteers.

The objective of this analysis was to explore exposure-response modeling of data from a thorough QT (TQT) study of tolterodine in CYP2D6 extensive (EMs) and poor metabolizers (PMs). Crossover treatments of the TQT study included the recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo. The concentration-response relationships for the QTc effects of moxifloxacin and tolterodine were described using a linear model with baseline effect, placebo effect, and a drug effect. The mixed effects modeling approach, using the first order conditional estimation method, was implemented in NONMEM. Simulated data from 250 trial replicates were used for limited predictive check and to describe the expected extreme responders in this study, under the derived model and point estimates. Modeling results for tolterodine showed linear concentrationdependent increases in QTc interval, with no difference in slopes between EMs and PMs. Modelpredicted QTc prolongations for tolterodine and moxifloxacin were consistent with their respective observed mean results. No subjects were predicted to have increases of > 60 milliseconds (ms); the predicted incidence of borderline QTc increases (> 30 and ≤ 60 ms) remained low at the supratherapeutic tolterodine dose in both PMs (9.1%) and EMs (3.9%). In conclusions, this analysis supports our clinical experience that tolterodine does not have a clinically significant effect on QT interval.

Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine.

OBJECTIVE: Fesoterodine, a new antimuscarinic agent for overactive bladder, undergoes immediate and extensive hydrolysis by nonspecific esterases to 5-hydroxymethyl tolterodine (5-HMT), the metabolite principally responsible for its antimuscarinic activity. Formation of 5-HMT does not require cytochrome P450 (CYP)-mediated metabolism, but its further metabolism and inactivation involves CYP3A4 and CYP2D6 isoenzymes. Subject age, gender, and race can play a key role in inter-subject variability in pharmacokinetics and thus efficacy and safety of drugs. This article examines the effects of age, gender, and race on the pharmacokinetics and pharmacodynamics of fesoterodine. METHODS: Data from two randomized, double-blind, placebo-controlled, parallel-group trials in healthy subjects are presented: Study 1 investigated the effects of race (white vs. black men) and Study 2 investigated the effects of age (young vs. old men) and gender (elderly men vs. elderly women) on the pharmacokinetics and pharmacodynamics of single doses of fesoterodine 8 mg. In both studies, the primary endpoints were area under the concentration-time curve up to the last sample (AUC0-tz) and maximum concentration (Cmax) of 5-HMT in plasma. Pharmacodynamic variables included spontaneous salivary secretion (Studies 1 and 2) and residual urine volume (Study 2 only). The two studies included 5 groups of 16 subjects each (randomized 3 : 1 to fesoterodine or placebo): white men aged 18 - 45 years, black men aged 18 - 45 years (Study 1); young white men aged 18 - 40 years, elderly white men aged > 65 years, and elderly white women aged > 65 years (Study 2). RESULTS: There were no clinically meaningful differences in the primary endpoints between white and black subjects or between young white men, elderly white men, and elderly white women. Mean AUC0-tz was 70.7 ng/ml x h in whites and 64.1 ng/ml x h in blacks; mean Cmax was 6.1 and 5.5 ng/ml in whites and blacks, respectively. Mean AUC0-tz in young white men, elderly white men, and elderly white women was 49, 48, and 54 ng/ml x h, respectively; mean Cmax in young white men, elderly white men, and elderly white women was 4.1, 3.8, and 4.6 ng/ml, respectively. Consistent with the anticholinergic pharmacology of fesoterodine, declines in salivary volume were observed in both studies, and elevations in residual urinary volume were observed, especially in elderly subjects, in Study 2. Fesoterodine was well tolerated, with common adverse events such as headache and dry mouth recognized as antimuscarinic class effects. CONCLUSIONS: Subject demographics, such as age, gender, and race, do not have a clinically meaningful effect on 5-HMT pharmacokinetics or pharmacodynamics after single-dose administration of fesoterodine 8 mg; thus, no dosage adjustment is required for fesoterodine based on age, gender, or race.

Thorough QT study with recommended and supratherapeutic doses of tolterodine.

The objective of our study was to determine the QTc effects of tolterodine. A crossover-design thorough QT study of recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo was performed. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on days 1-4; time-matched baseline ECGs were taken on day 0. Mean placebo-subtracted change from baseline Fridericia-corrected QT (QTcF) during peak drug exposure on day 4 was the primary end point. Mean QTcF prolongation of moxifloxacin was 8.9 ms (machine-read) and 19.3 ms (manual-read). At recommended and supratherapeutic tolterodine doses, mean QTcF prolongation was 1.2 and 5.6 ms (machine-read), respectively, and 5.0 and 11.8 ms (manual-read), respectively. The QTc effect of tolterodine was lower than moxifloxacin. No subject receiving tolterodine exceeded the clinically relevant thresholds of 500 ms absolute QTc or 60 ms change from baseline. In conclusion, tolterodine does not have a clinically significant effect on QT interval.

Oral bioavailability and disposition of [14C]omapatrilat in healthy subjects.

The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This single-dose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of omapatrilat averaged 31%. Total body clearance of omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady-state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first-pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of omapatrilat. Plasma concentrations of omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.

Disposition and safety of omapatrilat in subjects with renal impairment.

BACKGROUND: Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic peptides and inhibits the renin angiotensin aldosterone system by simultaneously inhibiting neutral endopeptidase and angiotensin-converting enzyme. METHODS: Oral omapatrilat, 10 mg/d, was administered for 8 to 9 days to three groups of eight subjects with varying degrees of renal function (CLCR values, normal > or = 80; mild to moderate impairment < 80 to > or = 30; severe impairment < 30 mL/min/1.73 mL2) and to six subjects undergoing maintenance hemodialysis. Omapatrilat and its metabolites (phenylmercaptopropionic acid, S-methylomapatrilat, S-methylphenylmercaptopropionic acid, and cyclic S-oxide-omapatrilat) were quantified in plasma by a validated liquid chromatography/mass spectrometry method. The model, Cmax or AUC(0-T) = intercept + slope x CLCR, was tested for a possible linear correlation between Cmax (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CLCR. RESULTS: For omapatrilat and its inactive metabolites, phenylmercaptopropionic acid, S-methylomapatrilat, and S-methylphenylmercaptopropionic acid, the median times to peak plasma concentrations (tmax) were 1.5 to 2, 2 to 3, 2.5 to 3.5, and 7 to 10 hours, respectively, and were independent of renal function. After Cmax attainment, plasma concentrations declined rapidly to about 10% of Cmax values. Cyclic S-oxide-omapatrilat, a potentially active metabolite, was undetectable at all sampling time points. Hemodialysis did not decrease circulating levels of omapatrilat. There was minimal accumulation of omapatrilat and phenylmercaptopropionic acid and moderate accumulation of the S-methylated metabolites. For omapatrilat and S-methylphenylmercaptopropionic acid, neither Cmax nor AUC(0-T) was CLCR dependent. However, AUC(0-T) for phenylmercaptopropionic acid and both the Cmax and AUC(0-T) for S-methylomapatrilat were CLCR dependent. CONCLUSIONS: The pharmacokinetics of omapatrilat, the only clinically relevant active compound studied, was independent of CLCR. For patients with reduced renal function, adjusting initial omapatrilat dose is not suggested. Hemodialysis did not significantly contribute to the clearance of omapatrilat. The long-term pharmacodynamic response to omapatrilat will dictate dose-adjustment needs.

Modeling the route of administration-based enhancement in the brain delivery of EAB 515, studied by microdialysis.

EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'biphenyl]-3-propanoic acid) is an extremely hydrophilic N-methyl-D-aspartate antagonist. It shows marked CNS activity, in that it is a potent neuroprotector in models of cerebral ischemia, and also demonstrates social and non-social behavioral alteration following systemic administration in animals. Because of its high degree of ionization at physiologic pH, one would not expect appreciable brain uptake of EAB 515 across tight junctions of the blood-brain barrier. This is in contrast to its pharmacologic effect as well as brain/plasma ratios measured during systemic administration in rats. These observations lead us to investigate other transport pathways that might account for its brain uptake. Such mechanistic information is imperative in rational drug delivery and drug design strategies. Upon intracerebroventricular administration, the observed steady-state cortical extracellular fluid concentrations of EAB 515 were over 100-fold higher than those observed following intravenous administration, when normalized for the dosing rate. This increased distribution into the brain, based upon the route of administration, suggests the transport of drug directly between the cerebrospinal fluid and the brain extracellular space. The parameters of the model that adequately describes the data obtained from the two routes of administration in individual animals were estimated. The clinical significance of these results is in the use of intracerebroventricular administration for enhanced brain delivery of hydrophilic drugs that poorly cross the blood-brain barrier.

High-performance liquid chromatographic analysis of (S)-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (EAB 515) in brain and blood microdialysate (on-line) and in plasma ultrafiltrate of freely moving rats.

(S)-alpha-Amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (EAB 515, I), a competitive antagonist of the N-methyl-D-aspartate receptor, has significant pharmacological activity in the central nervous system (CNS). An extremely sensitive and selective analytical method was developed for the simultaneous analysis of I and its hydroxylated analog (RDC, II) in the microdialysate (MD) and plasma ultrafiltrate (UF) of rats. Microdialysis was used for in vivo sampling of unbound drug in the CSF, cortical extracellular fluid and in the blood of freely moving rats. Compound II was used for retrodialysis-based in vivo calibration of microdialysis probes to estimate the recovery of I. Compound I, being extremely hydrophilic with a high degree of ionization at the physiological pH of 7.4, has limited access to the brain regions. This, combined with its low microdialysis recovery, made the estimation of low brain concentrations of I a challenge. The analytes in MD and UF were separated (within 5 min) by reversed-phase HPLC on a 250 x 4.6 mm I.D. Maxsil 5 microns RP-2 column, and fluorescence of the eluent was monitored at 255 nm (lambda ex) and 320 nm (lambda em). A 0.09% (v/v) aqueous solution of trifluoroacetic acid (1 ml/min) was used as the mobile phase. The response for I in MD and UF samples was linear from 5 to 2000 ng/ml and from 20 to 10,000 ng/ml, respectively. The between-run (n = 6) and within-run (n = 3) variability of the assay was < 15%. Plasma-protein binding of I (fu = 0.68) was determined to be linear from 0.1 to 10 micrograms/ml. The analytical sensitivity, precision and accuracy of this method was suitable for the characterization of the pharmacokinetics and the CNS distribution of I, following administration of intravenous (i.v.) infusion, single i.v. bolus and multiple i.v. bolus doses of I to freely moving rats, with continuous microdialysate sampling of multiple tissues and simultaneous on-line HPLC analysis. Pharmacokinetic parameters for I, as determined from concentrations in blood MD samples with on-line analysis, were in good agreement with those estimated from concentrations in the UF of plasma samples obtained by conventional sampling.

Investigation of the distribution of EAB 515 to cortical ECF and CSF in freely moving rats utilizing microdialysis.

A freely moving rat model was developed to study the CNS distribution of EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid). Microdialysis (MD) in the frontal cortex (FrC) and in the lateral ventricle (LV) of the rat brain was performed to measure the levels of EAB 515 in the cortical extracellular fluid (ECF) as well as in the cerebrospinal fluid (CSF). The femoral artery and femoral vein were cannulated for serial blood sampling and intravenous (i.v.) drug administration, respectively. EAB 515 was also administered via the intracerebroventricular (icv) route in a cross-over experiment. The in vivo recovery of EAB 515 across the MD probes was determined by simultaneous retrodialysis (RD) performed using a hydroxylated analog of EAB 515, as the RD calibrator (RDC). An extremely sensitive and selective on-line HPLC system with native fluorescence detection was developed for the simultaneous analysis of EAB 515 and RDC in microdialysate samples from rat CSF and cortical ECF. Unbound concentrations of EAB 515 in the rat plasma were determined by direct injection of plasma ultrafiltrate onto the HPLC column. The validity of the use of RDC as the RD calibrator was demonstrated by comparing the results of zero-net flux (ZNF) analysis simultaneously in some experiments. After constant rate i.v. infusion in rats (n = 12) for 900 min, the average (S.D.) ratio of the levels of EAB 515 in the CSF to those in plasma (Ccsf.iv/Cp) was determined to be 17.7 (7.8)% and that in the cortex relative to plasma (Ccortex.iv/Cp) was 8.3 (4.8)%.(ABSTRACT TRUNCATED AT 250 WORDS)