Biomedical subjects

R L Lalonde

Publications and source records attributed to R L Lalonde.

At least 19 recordsLinked to original sources

PubMed2007

Nontraditional approaches to first-in-human studies to increase efficiency of drug development: will microdose studies make a significant impact?

Much has been written recently about low productivity in the pharmaceutical industry and the high cost of drug development. Over a 10-year period ending in 2000, only approximately 11% of compounds tested in humans across 10 large pharmaceutical companies were eventually approved for marketing in the United States and/or Europe. Attrition was highest during phase II (62%) but still significant in phase III (45%) and at the time of registration (23%). Clearly, given the high cost and time required for clinical development, these late-stage failures are unsustainable.

Clinical Trials, Phase I as Topic↗

PubMed2000

Population pharmacokinetics of pemetrexed disodium (ALIMTA) in patients with cancer.

PURPOSE: To evaluate the population pharmacokinetics of pemetrexed disodium in cancer patients enrolled in four different open-label, multicenter, nonrandomized phase II studies. METHODS: Pemetrexed disodium was administered as a 10-min intravenous infusion (600 mg/m2) every 21 days. A total of four blood samples were to be collected each cycle per patient (n= 103 patients) during cycles 1 and 3. Plasma concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM to estimate pemetrexed disodium pharmacokinetic parameters (mean, and between- and within-patient variability) as well as relationships between the pharmacokinetic parameters and various patient-specific factors (demographic and physiologic data). RESULTS/CONCLUSIONS: The pharmacokinetics of pemetrexed disodium were best characterized by a two-compartment model with initial distribution and terminal elimination half-lives of 0.63 h and 2.73 h, respectively. The typical value of systemic clearance (CL) in liters per hour included a relationship to creatinine clearance (CrCL) with a slope of 0.0292. Typical values of central volume (V(c)), distributional CL (Q), and peripheral volume (V(p)) were 11.3 1, 3.21 l/h, and 5.20 l, respectively. Between-patient variability was 19.6%, 15.6%, and 21.7% for CL, V(c), and V(p), respectively. A combined additive/proportional error model was used to describe residual variability, with a coefficient of variation of 23.7% for the proportional component and a standard deviation of 0.0410 microg/ml for the additive component. Significant patient-specific factors on CL were calculated CrCL, body weight, and to a lesser extent alanine transaminase and folate deficiency. Gender and body weight were significant factors on V(c) while both body surface area and albumin were significant factors on V(p). In conclusion, population pharmacokinetic modeling revealed relationships between pharmacokinetic parameters and various patient specific factors.

Adult↗

PubMed2000

Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process: experience at Parke-Davis.

BACKGROUND: Continued scepticism about the benefits of population pharmacokinetics and/or population pharmacodynamics, here referred to collectively as the population approach, hampers its widespread application in drug development. At the same time the sources of this scepticism have not been clearly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug development at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here. METHODS: All drug development programmes conducted over the past 10 years that included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared together with a brief description of how the resulting information was used in each drug development programme. These synopses were forwarded to relevant members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses. RESULTS: The most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Application (NDA) submission the analyses resulted in information that was included in approved or proposed labelling. In almost half of the cases summarised here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development programmes. In many of these cases the information was serendipitous. It is also noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans. CONCLUSIONS: Use of the population approach, even when applied retrospectively, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptional efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.

Data Collection↗

PubMed1999

Mixed-effects modeling of the pharmacodynamic response to the calcimimetic agent R-568.

OBJECTIVE: The parathyroid cell calcium receptor is a novel drug target for affecting parathyroid hormone (PTH) secretion and for treating hyperparathyroidism. R-568 is a calcium receptor agonist that inhibits PTH secretion and increases calcitonin release in preclinical studies. The objective of this study was to evaluate the effect of R-568 on PTH plasma concentrations in humans. METHODS: Eighteen healthy postmenopausal women were included in the study. Single ascending oral doses of 10 to 400 mg were administered in a randomized, placebo-controlled double-blind trial. PTH plasma concentrations were measured for up to 120 hours after each dose. RESULTS: R-568 caused a dose-dependent decrease in plasma PTH, with peak effect observed within 1/2 to 2 hours after dosing. The maximum effect did not increase beyond doses from 80 to 160 mg, but duration of response increased at higher doses. An indirect-response model was developed to estimate the rates of input and output of the active moiety(ies), the inhibitory effect on PTH secretion, and the circadian variability in PTH. Population parameter estimates were 3.02 hour-1 and 0.49 hour-1 for rates of input and output of the active moiety(ies), respectively, IA50 (the unscaled amount of R-568 associated with 50% of Emax) was 16.3 mg, Emax (the maximum effect caused by R-568 expressed as a fraction of the rate of PTH secretion in the absence of any drug effect) was 89%, CPTH(baseline) (the baseline PTH plasma concentration in the absence of any drug effect) was 34.6 pg/mL, KePTH (the elimination rate constant for PTH) was 1.73 hour-1, amplitude of the circadian variability in PTH secretion was 5.8%, and the time of peak PTH secretion occurred at about 6 PM. Intersubject variability in parameter estimates ranged from 7% to 121%, and residual variability was 22%. CONCLUSION: The model correctly described the onset, extent, and duration of effect on PTH after a wide range of doses of R-568.

Administration, Oral↗

PubMed1999

Clinical comparability of albuterol delivered by the breath-actuated inhaler (Spiros) and albuterol by MDI in patients with asthma.

STUDY OBJECTIVE: This study compares the efficacy and safety of one and two actuations of albuterol sulfate powder delivered via a breath-actuated, effort-assisted, investigational inhaler (Spiros, Dura Pharmaceuticals, Inc) and albuterol delivered via a conventional propellant-driven metered dose inhaler (Ventolin, Glaxo, Inc). DESIGN: Randomized, double-blind, placebo-controlled, 5-way crossover study. PARTICIPANTS: Sixty patients with mild-to-moderate asthma (FEV1 59% predicted) were enrolled and 44 completed the study. MEASUREMENTS AND RESULTS: FEV1 values over 6 hours were analyzed by ANCOVA and the Finney relative potency model. The relative potency of the inhalers (albuterol MDI: albuterol DPI) was 1.132 (90% CI, 0.680 to 2.252) indicating 1.132 actuations of albuterol MDI provided the same bronchodilation as one actuation of albuterol DPI. ANCOVA analyses further indicated that there were no significant differences between the two delivery systems with respect to FEV1, FVC, FEF25-75%, or PEF. Both inhalers had similar effects on serum potassium levels, QTc interval, blood pressure, and heart rate. CONCLUSIONS: In patients with mild-to-moderate asthma in this study, the albuterol DPI was determined to be therapeutically comparable to albuterol MDI in the delivery of one and two actuations of albuterol.

Administration, Inhalation↗

PubMed1999

Comparison of different methods to evaluate population dose-response and relative potency: importance of interoccasion variability.

Different mixed-effects models were compared to evaluate the population dose-response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose-response and relative potency, there are important differences in the assumptions made by each method.

Administration, Inhalation↗

PubMed1998

Truncated area under the curve as a measure of relative extent of bioavailability: evaluation using experimental data and Monte Carlo simulations.

PURPOSE: The use of truncated areas under the curve (AUCs) could be a significant advantage for bioequivalence studies of drugs with long half-lives. The purpose of this study was to evaluate the performance of truncated AUCs as measures of relative extent of bioavailability using a large database of experimental data and Monte Carlo simulations. METHODS: The experimental data consisted of 123 single-dose, 2-treatment, crossover studies with at least 18 subjects/study. Monte Carlo techniques were also used to simulate studies that reflected a wide variety of experimental conditions. AUCs were calculated over different time intervals and the standard two one-sided t tests procedure was used to assess bioequivalence. RESULTS: The experimental data showed that conclusions concerning bioequivalence were identical between AUCs truncated at four times the time of peak concentration (Tmax) and AUCs extrapolated to infinity (AUC(inf)) in 120/123 or 97.6% of studies. There was little change in the intra-subject CVs for AUCs truncated at 3*Tmax or later. The results of Monte Carlo simulations were generally consistent with the experimental data and showed that AUCs truncated at 72 hours (AUC(0-72)) performed well compared to AUC(inf) as measures of bioequivalence for drugs with long half-lives. CONCLUSIONS: Based on both the experimental and simulated data, AUCs truncated after the absorption phase perform well as measures of relative extent of bioavailability. Truncated AUCs offer a particular advantage for drugs with long half-lives and these results indicate that it would be reasonable to limit the sample collection period to 72 hours in bioequivalence studies of oral formulations.

Biological Availability↗

PubMed1998

A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam.

PURPOSE: The objective of this study was to compare the pharmacokinetics and cognitive effects of a new diazepam (DZP) rectal gel (Diastat) with intravenously administered DZP. METHODS: Twenty healthy volunteers were enrolled in a single-blind, randomized, double-dummy, two-period, crossover study. Subjects received either 15 mg of DZP rectal gel or 7.5 mg of DZP by intravenous infusion. Blood samples for DZP and desmethyldiazepam analysis were obtained before the dose and from 3 min to 240 h after the dose. Heart rate and blood pressure were measured over the first 24-h period. Subjects also completed five repetitions of a neuropsychological test battery over the first 8-h period. RESULTS: Diazepam rapidly appeared in plasma after rectal administration, exceeding 200 ng/mL within 15 min and reaching an initial maximum of 373 ng/ml at 45 min and a second maximum of 447 +/- 91.1 ng/ml at approximately 70 min. The absolute bioavailability of DZP rectal gel was 90.4%. Subjects receiving intravenous DZP were less alert and performed less efficiently on the WAIS Digit Symbol test 6 min after the dose. Subjects receiving DZP rectal gel performed less well on the WAIS Digit Span test 1 h after the dose and required more time to complete the Letter Cancellation and Grooved Pegboard tests 1 and 2 h after drug administration. CONCLUSIONS: Diastat displayed rapid, consistent absorption and was well tolerated. Alterations in cognition were mild and dissipated within 4 h of drug administration. This new rectal drug-delivery system offers an easy, safe, and bioavailable method to administer DZP.

Administration, Rectal↗

PubMed1996

Population pharmacokinetics of terfenadine.

PURPOSE: After oral administration of terfenadine, plasma concentrations of the parent drug are usually below the limits of quantitation of conventional analytical methods because of extensive first-pass metabolism. Data are usually reported on the carboxylic acid metabolite (M1) but there are no published reports of pharmacokinetic parameters for terfenadine itself. The present study was undertaken to evaluate the population pharmacokinetics of terfenadine. METHODS: Data from 132 healthy male subjects who participated in several different studies were included in this analysis. After an overnight fast, each subject received a single 120 mg oral dose of terfenadine; blood samples were collected for 72 hours. Terfenadine plasma concentrations were measured using HPLC with mass spectrometry detection and M1 plasma concentrations were measured using HPLC with fluorescence detection. A 2-compartment model was fitted to the terfenadine data using NONMEM; terfenadine and M1 data were also analyzed by noncompartmental methods. RESULTS: Population mean Ka was 2.80 hr-1, Tlag was 0.33 hr, Cl/F was 4.42 x 10(3) 1/hr, Vc/F was 89.8 x 10(3) 1. Q/F was 1.85 x 10(3) 1/hr and Vp/F was 29.1 x 10(3) 1. Intersubject CV ranged from 66 to 244% and the residual intrasubject CV was 21%. Based on noncompartmental methods, mean terfenadine Cmax was 1.54 ng/ml, Tmax was 1.3 hr, t1/2 lambda Z was 15.1 hr, Cl/F was 5.48 x 10(3) 1/hr and V lambda Z/F was 119.2 x 10(3) 1. M1 concentrations exceeded terfenadine concentrations by more than 100 fold and showed less intersubject variability. CONCLUSIONS: Terfenadine disposition was characterized by a 2-compartment model with large intersubject variability, consistent with its significant first-pass effect.

Adult↗

PubMed1992

Two- and four-day rifampin chemoprophylaxis regimens induce oxidative metabolism.

The effects of two short-term chemoprophylaxis regimens of rifampin (2 or 4 days) on oxidative metabolism were investigated in 14 healthy subjects. Seven subjects received 600 mg of rifampin twice daily on study days 6 and 7 (group A), and seven subjects received 600 mg of rifampin once daily on days 4, 5, 6, and 7 (group B). Antipyrine (18 mg/kg of body weight) was administered orally on days 1, 8, and 15. Short-term rifampin regimens increased oral clearance of antipyrine in both groups compared with the baseline value (P less than 0.05), and group B displayed a larger percent increase over the baseline value than group A did (70.5 +/- 14.3 versus 33.1 +/- 18.1; P less than 0.05). The partial metabolic clearance (CLM) of antipyrine to 3-hydroxymethylantipyrine (HMA) on day 8 increased 71 and 108% for regimens A and B, respectively (P less than 0.05 for both). The corresponding increases in CLM to norantipyrine (NORA) were 57 and 98% (P less than 0.05 for both). CLM to 4-hydroxyantipyrine (OHA) on day 8 increased 64% for regimen A (P = 0.08) and 97% for regimen B (P less than 0.05) compared with the baseline. Although CLM to HMA and OHA on day 15 remained greater than 50% over the baseline with both regimens, CLM to NORA on day 15 was less than 25% over the baseline with both regimens. Thus, both short-term rifampin chemoprophylaxis regimens increased antipyrine clearance for at least 1 week. The increase tended to be higher with the 4-day regimen. The pattern observed for the CLMS suggests that more than one P-450 enzyme is affected.

Administration, Oral↗

PubMed1991

Solid-phase extraction and direct high-performance liquid chromatographic determination of metoprolol enantiomers in plasma.

A method is described by which underivatized metoprolol enantiomers in plasma can be quantitated by high-performance liquid chromatography with fluorescence detection. Samples are prepared for injection using a simple solid-phase extraction procedure which is essentially 100% efficient for all analytes. The metoprolol enantiomers are resolved using a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase and a hexane-ethanol-diethylamine mobile phase. Samples were tested for adaptability to autoinjection and found to be stable for at least 16 h after reconstitution in mobile phase. The automated method was determined to be precise and accurate for enantiomer concentrations as low as 10 ng base per ml and was successfully employed in a pharmacokinetic investigation.

Chromatography, High Pressure Liquid↗

PubMed1990

Labetalol pharmacokinetics and pharmacodynamics: evidence of stereoselective disposition.

Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with cimetidine administration (58.7 +/- 23.3 to 32.9 +/- 13.2 ml/min/kg; p less than 0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 +/- 5.3 to 17.7 +/- 3.7 ml/min/kg; p less than 0.05), but the volume of distribution was unchanged. Labetalol caused significant beta-blockade for 8 hours after the last oral dose, but cimetidine did not alter pharmacologic response. The Emax model provided a good description of the concentration-effect relationship. At peak labetalol concentrations after oral administration, (R,R)-labetalol concentrations were significantly lower than those of the other three stereoisomers (p less than 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p less than 0.05) for only the (S,R)-, (S,S)-, and (R,S)-isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)-labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)-labetalol.

Administration, Oral↗

PubMed1990

Effects of age on the protein binding and disposition of propranolol stereoisomers.

Previous studies of the effects of age on the disposition of propranolol have produced variable results. We evaluated the stereoselective disposition and protein binding of propranolol enantiomers in 10 young (mean age, 28 years) and 10 older (mean age, 64 years) healthy subjects. After receiving racemic propranolol orally for 6 days, the oral clearances of d-propranolol and l-propranolol were lower by 13% and 17% in the older group compared to the young group, but these differences were not statistically significant. The older subjects had higher alpha 1-acid glycoprotein concentrations (p less than 0.05) and lower unbound fractions of l-propranolol (p less than 0.05). After protein binding was accounted for, the unbound oral clearance of each enantiomer was similar in both groups. l-Propranolol was more highly protein bound than d-propranolol (p less than 0.05) in both young and older subjects. The unbound oral clearance d/l ratio was not different from unity in either group, indicating that the stereoselective differences in oral clearance were largely attributable to the stereoselective differences in protein binding.

Adult↗

PubMed1990

Effects of calcium channel blockers on the pharmacokinetics of propranolol stereoisomers.

Diltiazem and verapamil inhibit oxidative drug metabolism both in vivo and in vitro. We compared their effects on the stereoselective pharmacokinetics and protein binding of propranolol in 12 subjects. After 6 days of coadministration with racemic propranolol, diltiazem caused decreases of 27% and 24% in d-propranolol and 1-propranolol oral clearances, respectively (p less than 0.05 versus control). With verapamil, d-propranolol oral clearance decreased 32% (p less than 0.05), and 1-propranolol oral clearance decreased 26% (p less than 0.05). The unbound fraction of d-propranolol was higher than that of 1-propranolol (p less than 0.05), but the protein binding was not altered by diltiazem or verapamil. Both drugs therefore decreased the unbound oral clearance of each propranolol enantiomer (p less than 0.05). Verapamil caused a stereoselective effect and increased the d/l ratio of propranolol serum concentrations (p less than 0.05) and decreased the d/l ratio of oral clearance (p less than 0.05).

Adult↗

PubMed1990

Altered beta-adrenergic sensitivity and protein binding to 1-propranolol in the elderly.

The elderly are reported to be less sensitive to the beta-blocking effects of propranolol. However, age-related changes in the stereoselective pharmacokinetics or protein binding of propranolol enantiomers could have confounded the results of previous studies because only 1-propranolol contributes significantly to the beta-blocking effects of the racemate. To avoid these confounding variables, we studied 10 young (mean 28 years) and 10 elderly (mean 64 years) subjects, and determined the cardiac beta-receptor sensitivity in terms of unbound, active 1-propranolol. The doses of isoproterenol required to increase heart rate (HR) by 25 beats/min were determined before and during a continuous infusion of propranolol. The serum concentration of 1-propranolol was determined by enantioselective high-performance liquid chromatography (HPLC), and the unbound fraction was determined by equilibrium dialysis. The apparent in vivo receptor dissociation constant for unbound 1-propranolol increased from 0.066 +/- 0.047 ng/ml in the young to 0.218 +/- 0.264 ng/ml in the older group (p less than 0.05). The unbound fraction was decreased in the older subjects (0.141 +/- 0.023 vs. 0.121 +/- 0.025, p less than 0.05) because of an increase in alpha 1-acid glycoprotein concentration (55 +/- 11 mg/dl vs. 72 +/- 19 mg/dl, p less than 0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (rs = 0.76, p less than 0.05) and to unbound 1-propranolol (rs = 0.45, p less than 0.05). We conclude that the older subjects have (a) decreased sensitivity to the beta-blocking effects of 1-propranolol and to the agonist effects of isoproterenol, and (b) a lower unbound fraction of 1-propranolol.

Adult↗

PubMed1990

Dilevalol: an overview of its clinical pharmacology and therapeutic use in hypertension.

Dilevalol is a novel antihypertensive drug that combines nonselective beta blockade with selective beta 2-receptor agonist activity. Its antihypertensive effect is mediated through arterial vasodilation and a decrease in systemic vascular resistance. At rest, dilevalol has little effect on heart rate or cardiac output. The drug is rapidly and completely absorbed but undergoes significant first-pass hepatic extraction. Its elimination half-life of approximately 12 hours allows for once-daily administration. In controlled clinical trials, dilevalol was at least as effective as angiotensin-converting enzyme inhibitors and comparable to beta blockers in antihypertensive efficacy. Preliminary data indicate that dilevalol reverses left ventricular hypertrophy in some patients. It does not adversely affect renal function and may have a favorable effect on plasma lipids, especially high-density lipoprotein cholesterol. The agent is usually well tolerated and may prove to be a useful addition to our antihypertensive drugs.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

The effects of encainide versus diltiazem on the oxidative metabolic pathways of antipyrine.

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p less than 0.05) and increased half-life from 12.7 to 15.9 hours (p less than 0.05). Diltiazem reduced the formation rate constants for 3-hydroxymethylantipyrine by 27% (p less than 0.05) and 4-hydroxyantipyrine by 37% (p less than 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 less than p less than 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half-life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.

Adult↗

PubMed1989

Pharmacokinetics and pharmacodynamics of dilevalol.

The pharmacokinetics and pharmacodynamics of dilevalol, the R,R stereoisomer of labetalol, were evaluated in nine subjects. Dilevalol was given as a single 50 mg intravenous dose and as a 400 mg daily oral dose for 7 days. To study the effects of hepatic enzyme inhibition, each subject received dilevalol in the presence of and absence of cimetidine. Cardiac beta-blockade was assessed by use of standardized treadmill tests for 48 hours after oral dilevalol. The three-compartment model analysis showed that systemic clearance (29.8 +/- 5.7 ml/min/kg), volume of distribution (16.6 +/- 4.1 L/kg), and terminal half-life (11.7 +/- 2.7 hours) were not altered by cimetidine. However, there was a 20% increase in the area under the curve (p less than 0.05) and an 11% increase in systemic bioavailability (p less than 0.05) after oral administration. Dilevalol caused significant cardiac beta-blockade for more than 24 hours, but these effects were not altered by cimetidine. The pharmacokinetic changes are consistent with a decrease in first-pass extraction of a high clearance drug.

Administration, Oral↗