J. Robert Powell

Intraindividual variability in theophylline pharmacokinetics: Statistical verification in 39 of 60 healthy young adults

After administering a single 300 mg dose of theophylline in oral solution to 12 healthy adults, the dose-normalized area under the plasma concentration-time curve was 97.2±20.1 % (mean±SD) of that after giving a 500 mg dose and statistically indistinguishable. Similarly, these areas multiplied by the individuals terminal disposition rate constant (β) were statistically indistinguishable between 300 and 500mg doses (99.1±10.3%), giving no evidence of dose-dependence for theophylline kinetics at the levels below 15 μg/ml observed in these individuals. After an intravenous dose, a shortlived distribution phase (t1/2α) is sometimes seen. An a phase, however, is hardly discernible in over 250 profiles arising from oral doses administered during five single dose bioavailability studies. Almost all such profiles appear to follow single-compartment model predictions. With precautions to avoid a potential a phase, a terminal log-linear slope can be fitted by least squares analysis with a relative standard error in the slope determination almost always less than 6%. Covariance analysis confirms statistically that 39 of the 60 participating individuals varied in their β on the different occasions each was required to take a dose during the course of a crossover bioavailability trial. In one study, even though each individual was observed on only two occasions, 9 out of 12 showed statistically identifiable variation in β. Fluctuations in β of 60% can be seen. Changes of 30% or greater are common and can occur within 3 or 4 days. Thus real, large, and potentially frequent changes in β of theophylline have been identified in a majority of normal subjects. These changes do not appear to be confined to either sex, to smokers or nonsmokers, or to heavier or lighter individuals. No chronological pattern has, as yet, been recognized in the intraindividual variability in β.

Age and gender effects on ondansetron pharmacokinetics: Evaluation of healthy aged volunteers

Modest differences in the clearance of the 5HT3 antagonist, ondansetron, among different age groups were detected in two groups of healthy elderly volunteers, one group aged 61 to 74 years (“elderly”) and the other 75 to 82 (“aged”) years, in addition to young healthy subjects. Both a single 0.15 mg/kg intravenous dose and a single 8 mg oral dose were administered according to a randomized crossover design with a minimum 3‐day washout period between treatments. Mean plasma clearance decreased (young, 0.349 L/hr/kg; elderly, 0.279 L/hr/kg; aged, 0.214 L/hr/kg; p <0.05) with increasing age. Volume of distribution at steady state was unaffected by age (young, 1.81 L/kg; elderly, 1.94 L/kg; aged, 1.71 L/kg), resulting in increases in mean plasma half‐life (young, 3.4 hours; elderly, 4.5 hours; aged, 5.4 hours) and mean absolute bioavailability (young, 57%; elderly, 61%; aged, 69%) with increasing age. Female subjects cleared ondansetron more slowly than males (p < 0.05), resulting in higher absolute bioavailability. Ondansetron was well tolerated by all age groups with no increase in the number of adverse events observed in older volunteers.

Effect of dose on phenytoin absorption

To determine the effect of dose on phenytoin bioavailability, a single intravenous 15‐mg/kg dose, single oral doses of 400, 800, and 1,600 mg, and 1,600 mg in divided doses (400 mg every 3 hr) were given to six healthy male subjects. Values of Vmax (maximum elimination rate) and Km (serum concentration at which rate of elimination is one half the maximum rate) from the intravenous dose were used to determine the extent of absorption. Although no statistically significant difference in extent of phenytoin absorption was detected, the time to reach maximum phenytoin serum concentrations increased from 8.4 hr for the 400‐mg dose and 13.2 hr for the 800‐mg dose to 31.5 hr for the 1,600‐mg dose. After the 400, 800, and 1,600‐mg doses and 1,600‐mg divided doses, the serum concentration peaks were 3.9, 5.7, 10.7, and 15.3 mg/l. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to slow dissolution and continued absorption from the colon. Due to prolonged absorption of phenytoin, it may be necessary to use larger oral than intravenous loading doses to achieve the same maximum phenytoin serum concentrations.

Effect of sodium acid pyrophosphate on ranitidine bioavailability and gastrointestinal transit time

During development of a ranitidine effervescent oral solution dosage form, a marked decrease was observed in the extent of ranitidine absorption relative to the conventional oral tablet. Two studies were conducted in healthy volunteers to confirm the involvement of an excipient, SAPP (sodium acid pyrophosphate), and the mechanism of interaction, altered gastrointestinal transit. The first study (n = 12) involved single-dose crossover comparisons of (A) 150 mg ranitidine with 1132 mg SAPP versus (B) 150 mg ranitidine and (C) 150 mg ranitidine with all the effervescent tablet excipients except SAPP versus (D) a 150-mg ranitidine effervescent tablet, all administered as oral solutions. Serum ranitidine AUC, Cmax, and tmax were compared using two one-sided t test 90% confidence intervals (CI). Comparing treatments A to B and D to C, all 90% CI were below the 80–120% range, indicating significantly less extensive ranitidine absorption (54% based on AUC) from the oral solutions containing SAPP. The second study (n = 12) was a single-dose crossover comparing 50 µCi 111InCl solutions with and without 1132 mg SAPP. Gastrointestinal transit times, determined by scintigraphic imaging, were compared between treatments. Gastric emptying time was unchanged, but small intestinal transit time was decreased to 56% in the presence of SAPP. More rapid small intestinal transit associated with an excipient of a solution dosage form apparently resulted in a decreased extent of ranitidine absorption. This observation contradicts the conventional wisdom that oral solutions are unlikely to fall short of bioequivalence relative to solid oral formulations.

Phenobarbital Pharmacokinetics and Bioavailability in Adults

Abstract: The pharmacokinetics and bioavailability of phenobarbital were examined in six healthy adult subjects after a 2.6 mg/kg intravenous and a 2.9 mg/kg oral dose. Serum concentrations of phenobarbital were followed by means of a high pressure liquid chromatographic assay for 21 days after drug administration. After the intravenous dose, the mean distribution half‐life was 0.18 hour and the mean elimination half‐life was 5.8 days. Mean total body clearance and mean renal clearance were 3.0 ml/hr/kg and 0.8 ml/hr/kg, respectively. The apparent volume of distribution was 0.60 liter/kg. After administration of phenobarbital tablets, the maximum phenobarbital serum concentration was 5.5 mg/liter at 2.3 hours after the dose. Adjusted absolute availability of phenobarbital from the tablets studied was 94.9 per cent (range 81–111.9 per cent). The elimination half‐life averaged 5.1 days for the oral dose. There was no evidence of autoinduction of phenobarbital elimination over the study period.

Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine

In this double‐blind, randomized, crossover, placebo‐controlled study, the effect of multiple oral doses of acetaminophen on lamotrigine disposition was examined in healthy volunteers. Eight volunteers received two single 300 mg oral doses of lamotrigine, administered 20 days apart. Acetaminophen (2.7 gm/day) or placebo was taken for 24 hours before and continued for 10 days after each lamotrigine dose. Area under the plasma concentration–time curve for lamotrigine [AUC(0‐∞)] and lamotrigine half‐life were statistically decreased by 20% (229.0 ± 62.5 μg · hr/ml versus 191.2 ± 42.1 μg · hr/ml, p < 0.01) and 15% (35.7 ± 9.3 hours versus 30.2 ± 7.3 hours, p < 0.01), respectively, when concurrently administered with acetaminophen. There was no significant difference in the peak plasma concentration or the time to reach peak plasma concentration. The percentage of the dose of lamotrigine recovered in the urine (total) was significantly higher during the acetaminophen treatment (65.9% ± 12.3% versus 72.5% ± 5.7%, p = 0.048). Acetaminophen seems to facilitate lamotrigine removal through a yet to be determined mechanism(s).

Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria.

The biovailability of theophylline from alcoholic and aqueous oral solutions was compared to that from an intravenous dose in 12 normal adults. The alcoholic elixir surprisingly gave rise to a significantly greater (114 ±14%, mean±sd amount absorbed than did the intravenous dose. The aqueous solution (99±8%) and intravenous dose were statistically indistinguishable in this respect, and, furthermore, the extent of absorption from a 300-mg dose of the aqueous solution was 99±10% of that from a 500-mg dose, and not statistically different. The aqueous solution was thus employed in three subsequent studies as a standard with which to compare 13 different types of theophylline tablets, all marketed in the United States. Of the 13 tablets, eight showed bioavailability statistically distinguishable from that of the standard. Nevertheless, for only two tablets could it be claimed with 95% confidence that the bioavailability was less than 95%. For none can it be stated at this confidence level that the bioavailability is less than 90%. Bioavailability studies should include criteria of clinical significance in addition to criteria of statistical significance. Contrary to the usual rationale behind choice of a bioavailability standard, nine of the 12 uncoated tablets appeared to allow more rapid absorption of theophylline than did the standard oral solution, an aqueous syrup. Increasing the dose of syrup decreased the rate of theophylline absorption. Orally administered drug solutions may have properties more absorption rate limiting than the disintegration of many brands of tablet.

Ranitidine at very large doses does not inhibit theophylline elimination

While most controlled studies in humans indicate that ranitidine does not alter drug metabolism, there is some evidence that ranitidine may have this property. If ranitidine does inhibit drug metabolism in a predictable manner, such an effect might be expressed at higher ranitidine doses. Our study was designed to contrast the effects of large doses of ranitidine (1200 and 4200 mg/day) and Cimetidine (1200 mg/ day) on theophylline elimination. Whereas Cimetidine decreased theophylline clearance in 11 of 12 subjects by a mean of 19.4%, neither ranitidine dose affected theophylline disposition. While case reports indicate ranitidine may inhibit theophylline metabolism specifically and drug metabolism in general, we were not able in our controlled study to detect any effect of ranitidine on theophylline elimination even at ranitidine doses up to fourteenfold greater than are generally prescribed.

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

BackgroundContinued 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.MethodsAll 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.ResultsThe 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.ConclusionsUse 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.

Clinical pharmacology of carvedilol in normal volunteers

The mechanism of the vasodilatory action of carvedilol (BM 14190), a new antihypertensive agent, was investigated in normal volunteers. Intra‐arterial blood pressure and ECG were monitored continuously. Carvedilol (1 mg/min for 15 minutes) produced a rapid reduction in blood pressure and a transient increase in heart rate. At the end of infusion, systolic and diastolic blood pressure were reduced by 23% (−32.3 mm Hg) and 18% (−13.6 mm Hg), respectively, whereas heart rate was not different from baseline. At the doses used, the hypotensive effect of carvedilol was greater than that of labetalol (36 and 72 mg in 15 minutes). Carvedilol and labetalol antagonized isoproterenol‐induced hypotension and tachycardia, at serum levels ≥8 and 20 mg/ml, respectively. Both drugs antagonized phenylephrine pressor effects. A similar degree of inhibition (25% of control) of pressor effects was observed for carvedilol and labetalol when their respective serum concentrations were 23 ng/ml and 80 ng/ml. Neither carvedilol nor labetalol had any effect on AII pressor responses. Carvedilol serum levels as high as 150 ng/ml failed to inhibit AII‐induced pressor responses. Our results suggest that at the doses used in this study, carvedilol has both α1‐ and nonselective β‐receptor blocking properties. Moreover, carvedilol is approximately three to five times more potent than labetalol in blocking α1‐ and β‐receptors and in reducing blood pressure.