Michael Mayersohn

A Novel Model for Prediction of Human Drug Clearance by Allometric Scaling

Sixty-one sets of clearance (CL) values in animal species were allometrically scaled for predicting human clearance. Unbound fractions (fu) of drug in plasma in rats and humans were obtained from the literature. A model was developed to predict human CL: CL = 33.35 ml/min × (a/Rfu)0.770, where Rfu is the fu ratio between rats and humans and a is the coefficient obtained from allometric scaling. The new model was compared with simple allometric scaling and the “rule of exponents” (ROE). Results indicated that the new model provided better predictability for human values of CL than did ROE. It is especially significant that for the first time the proposed model improves the prediction of CL for drugs illustrating large vertical allometry.

Interspecies prediction of human drug clearance based on scaling data from one or two animal species.

A data-driven approach was adopted to derive new one- and two-species-based methods for predicting human drug clearance (CL) using CL data from rat, dog, or monkey (n = 102). The new one-species methods were developed as CLhuman/kg = 0.152 · CLrat/kg, CLhuman/kg = 0.410 · CLdog/kg, and CLhuman/kg = 0.407 · CLmonkey/kg, referred to as the rat, dog, and monkey methods, respectively. The coefficient of the monkey method (0.407) was similar to that of the monkey liver blood flow (LBF) method (0.467), whereas the coefficients of the rat method (0.152) and dog method (0.410) were considerably different from those of the LBF methods (rat, 0.247; dog, 0.700). The new rat and dog methods appeared to perform better than the corresponding LBF methods, whereas the monkey method and the monkey LBF method showed improved predictability compared with the rat and dog one-species-based methods and the allometrically based “rule of exponents” (ROE). The new two-species methods were developed as CLhuman = arat-dog · W human0.628 (referred to as rat-dog method) and CLhuman = arat-monkey · W human0.650 (referred to as rat-monkey method), where arat-dog and arat-monkey are the coefficients obtained allometrically from the corresponding two species. The predictive performance of the two-species methods was comparable with that of the three-species-based ROE. Twenty-six Wyeth compounds having data from mouse, rat, dog, monkey, and human were used to test these methods. The results showed that the rat, dog, monkey, rat-dog, and rat-monkey methods provided improved predictions for the majority of the compounds compared with those for the ROE, suggesting that the use of three or more species in an allometrically based approach may not be necessary for the prediction of human exposure.

Thiopental disposition in lean and obese patients undergoing surgery.

The effect of obesity on the disposition kinetics of thiopental was studied in seven morbidly obese (age 25 to 46 years) and eight age-matched lean patients (age 25 to 43 years), undergoing primarily abdominal surgery. Based upon total (bound + free) thiopental concentrations, the average (±SD) volumes of distribution in the terminal disposition phase and at steady-state (Vβ and Vss) were significantly larger in the obese (7.94 ± 4.55 1/kg and 4.72 ± 2.73 1/kg, respectively) than in the age-matched lean patients (1.95 ± 0.63 1/kg and 1.40 ± 0.46 1/kg, respectively). Clearance of total thiopental, normalized for total body weight was not significantly different between the obese (0.18 ± 0.081 · h−1 · kg−1) and lean patients (0.2 ± 0.06 1 · h−1 · kg−1). However, total body clearance not normalized for total body weight was significantly larger in the obese (24.98 ± 14.87 1/h) than in the lean patients (11.86 ± 3.66 1/h). The elimination half-life of thiopental was significantly longer in the obese (27.85 h) than in the lean patients (6.33 h) and (his difference was primarily a function of the larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8 per cent to 27.6 per cent) was not correlated with the degree of obesity. The most appropriate means of comparing intrinsic metabolizing capacity (i.e., normalized vs. non-normalized for weight) between lean and obese subjects remains unresolved.

Bleomycin pharmacokinetics in man: II. Intracavitary administration

Disposition of bleomycin was studied in plasma and urine (14 patients) and ascites fluid (2 patients) after intraperitoneal (IP) and intrapleural (IPl) administration, by radioimmunoassay. Peak plasma bleomycin concentrations after 60 U/m2 in 12 patients ranged between 0.4 and 5.0 mU/ml. For those patients with creatinine clearances greater than 50 ml/min the composite terminal phase bleomycin plasma half-lives (±SD) for three ‘IPl’ and six ‘IP’ patients were 3.4±0.3 and 5.3±0.4 h, respectively. The composite IP plasma half-life was significantly longer than the IPl hal-life (P<0.001) and previously reported IV half-life (t1/2=4.0 ±0.6 h) (P<0.01). In patients with normal renal function, bleomycin excretion during the first 24 h was in most cases lower following intracavitary (IC) than following IV administration (21.7%±8.6% vs. 44.8%±12.6%, respectively) (P<0.005). Comparison of bleomycin plasma concentration time products normalized for dose and half-life for IV and IC administration allowed an estimate that about 45% of the IC bleomycin dosage is absorbed into the systemic circulation. When calculating the total systemic exposure to bleomycin for a patient we suggest using the sum of the IV dose and one-half of the IC dose.

Moricizine Bioavailability via Simultaneous, Dual, Stable Isotope Administration: Bioequivalence Implications

The relative bioavailability of a 200 mg film‐coated tablet of [12C]moricizine•HCl in comparison toa200 mg [13C6]moricizine•HCl oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine•HCl and [13C6]moricizine•HCl were determined by thermospray liquid chromatography‐mass spectrometry (LC‐MS) using [2H11]moricizine•HCl as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (% CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) μg/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration‐time curve (AUC), 1.58 (39%) versus 1.49 (37%) μg•h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t1/2, 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first‐pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cvε) afforded via the single‐period, dual‐isotope design. In contrast, a previous study using the conventional two‐period crossover design determined the cvε about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this study further illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design.

Bleomycin pharmacokinetics in man. I. Intravenous administration.

SummaryDisposition of bleomycin was studied in plasma and urine (14 patients) and ascites fluid (2 patients) after intraperitoneal (IP) and intrapleural (IPl) administration, by radioimmunoassay. Peak plasma bleomycin concentrations after 60 U/m2 in 12 patients ranged between 0.4 and 5.0 mU/ml. For those patients with creatinine clearances greater than 50 ml/min the composite terminal phase bleomycin plasma half-lives (±SD) for three ‘IPl’ and six ‘IP’ patients were 3.4±0.3 and 5.3±0.4 h, respectively. The composite IP plasma half-life was significantly longer than the IPl hal-life (P<0.001) and previously reported IV half-life (t1/2=4.0 ±0.6 h) (P<0.01). In patients with normal renal function, bleomycin excretion during the first 24 h was in most cases lower following intracavitary (IC) than following IV administration (21.7%±8.6% vs. 44.8%±12.6%, respectively) (P<0.005). Comparison of bleomycin plasma concentration time products normalized for dose and half-life for IV and IC administration allowed an estimate that about 45% of the IC bleomycin dosage is absorbed into the systemic circulation. When calculating the total systemic exposure to bleomycin for a patient we suggest using the sum of the IV dose and one-half of the IC dose.SummaryBleomycin plasma decay kinetics and urinary excretion were studied in nine patients after IV bolus injections of 13.7 to 19.9 U/M2. Radio-immunoassay was used to measure bleomycin in plasma and urine samples. The resulting plasma concentration versus time data for each patient and the combined data obtained from all patients were fitted to a multiexponential equation using a nonlinear regression computer program. Pharmacokinetic parameters derived from the mean of all individual patient parameters and the composite of all plasma decay data were similar. Bleomycin initial and terminal plasma half-lives and volume of distribution for all plasma decay data from eight patients with normal serum creatinies were 24.4±4.0 min, 237.5±8.5 min, and 17.3±1.5 L/M2, respectively. Mean 24-h urinary excretion accounted for 44.8±12.6% of the dose in seven patients who had normal serum creatinine values and complete urine collections. The total body clearance and renal clearance in these seven patients averaged 50.5±4.1 ml/min/M2 and 23.0±1.9 ml/min/M2, respectively. One patient with a serum creatinine of 1.5 mg% (normal 0.7 to 1.3 mg%) who was given 15.6 U/M2 had a terminal plasma halflife of 624 min, a volume of distribution of 36.3 L/M2, and 24-h urinary excretion of 11.6% of the dose. We conclude that bleomycin after intravenous bolus injection has a relatively short terminal phase plasma halflife and relatively large urinary elimination.

Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function

Three different studies were conducted to assess the pharmacokinetics of moclobemide in subjects with conditions complicating dose determination. The first examined the absorption and disposition of moclobemide in an elderly population and compared these with results obtained in a group of normal young subjects. No significant differences were found between the groups in the intravenous (i. v.) parameters of disposition, and no differences with regard to disposition of the metabolite, Ro 12‐8095. In addition, the minimum steady‐state concentrations of moclobemide and the main plasma metabolite did not differ between the elderly and younger patients. In the second study, clearance tests in patients with cirrhosis of the liver confirmed that hepatic function is drastically reduced in this group of patients; it is therefore possible that moclobemide absorption and distribution might be influenced. In only 3 of the 12 patients investigated, slowly declining plasma concentrations after administration pointed to a severely limited elimination capacity for moclobemide. In the remaining 9 subjects, average values of several parameters changed significantly (t1/2β, MRT and CI), whereas Vss and renal clearance were not significantly altered. In patients with kidney dysfunction, there were no differences in kinetics between patients undergoing hemodialysis and those who were not. Compared with normal healthy volunteers, no differences were found for renal patients, with the exception of the mean absorption time, which was significantly prolonged. From these studies it can be concluded that, pharmacokinetically, neither age nor renal impairment require adjusting the dosage of moclobemide. Patients with liver cirrhosis, however, need to have the usual dose reduced to one half or one third, or else the dosage intervals can be increased to prevent cumulation.

Isolation of monoclonal antibodies to phencyclidine from ascites fluid by preparative isoelectric focusing in the Rotofor

A monoclonal antibody to phencyclidine was developed, produced in mouse ascites fluid, and purified. The purification used only preparative-scale isoelectric focusing in the Rotofor and dialysis. In 4 h, 25% (4 mg) of the antibody from 10 ml of ascites fluid was purified to homogeneity while 63% of the total antibody was recovered.

Dermal Absorption of Camphor, Menthol, and Methyl Salicylate in Humans

Camphor, menthol, and methyl salicylate occur in numerous over‐the‐counter products. Although extensively used, there have been no estimates of human exposure following administration via dermal application. Furthermore, there is little information about the pharmacokinetics of those compounds. The authors report the plasma concentrations of the intact compounds as a function of dose following dermal patch application. Three groups of 8 subjects (4 male, 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were assayed using sensitive and selective gas‐chromatographic methods. For the 8‐patch group, the average maximum plasma concentrations (Cmax ± SD) were 41.0 ± 5.8 ng/mL, 31.9 ± 8.8 ng/mL, and 29.5 ± 10.5 ng/mL for camphor, menthol, and methyl salicylate, respectively. The corresponding values for the 4‐patch group were 26.8 ± 7.2 ng/mL, 19.0 ± 5.4 ng/mL, and 16.8 ± 6.8 ng/mL. The harmonic mean terminal half‐lives were 5.6 ± 1.3 hours, 4.7 ± 1.6 hours, and 3.0 ± 1.2 hours for camphor, menthol, and methyl salicylate, respectively. The 2‐patch group had measurable but low plasma concentrations of each compound. Low‐dose dermal application for an extended time results in low plasma concentrations of all 3 compounds. Four and 8 patches, when applied for 8 hours, gave measurable and nearly proportional plasma concentrations. Although unable to determine the absolute dermal bioavailability of these compounds, there appears to be relatively low systemic exposure to these potentially toxic compounds, even when an unrealistically large number of patches are applied for an unusually long time.

Clinical Pharmacokinetics of the Monoamine Oxidase-A Inhibitor Moclobemide

SummaryThere has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined.Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order).Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug.Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called ‘cheese effect’ is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.