Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up.

Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosour ea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Log-log plots of body weight (W; kg) vs total plasma clearance (CLtot,p; ml/min) and steady-state distribution volume (Vd,ss; l) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was greater than 97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p = 50.6 W0.957; Vd, ss = 1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLutot,p and Vd,uss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLutot,p = 71.7 W0.891; Vd,uss = 1.82 W0.966) were also high (r greater than or equal to 0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLutot,p, 3,160 vs 2,290 ml/min; Vd,uss, 110 vs 106 l. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.

The pharmacokinetic profile of RS-8359.

RS-8359 is very rapidly absorbed, metabolized and distributed following oral dosing, with significant concentrations of both parent drug and its principal metabolite appearing in plasma within 15 min. Plasma levels were linearly related to doses of up to 300 mg, beyond which absorption was diminished, perhaps due to a saturation effect. Clearance of RS-8359 is mainly through the renal system as the metabolite, and is virtually complete within 24 h. The kinetic profile of the drug best fits a two-compartment model, and mean residence time and half-life (beta) of the drug support a twice a day regimen for extended use. During multiple dosing twice a day for up to 6 weeks, steady state plasma drug levels were achieved within 48 h and there was no evidence of significant accumulation.

Dosage form design for improvement of bioavailability of levodopa III: Influence of dose on pharmacokinetic behavior of levodopa in dogs and Parkinsonian patients.

The relationship between the dose of levodopa and its pharmacokinetic behavior following intravenous and oral administration was investigated in dogs and parkinsonian patients. Six beagle dogs received single doses of 2.4, 4.8, and 9.6 mg of levodopa/kg iv and single doses of 4.8, 9.6, and 19.2 mg of levodopa/kg po in a crossover fashion on separate occasions. Three parkinsonian patients received single oral doses of approximately 3.8, 7.7, and 15.4 mg of levodopa/kg in a crossover test. Plasma samples were analyzed for intact levodopa and total dopamine. The relationship between the area under the plasma concentration-time curve (AUC) of levodopa and the intravenous dose to dogs was linear. However, in both dogs and patients, the relationship after oral dosing was nonlinear, with the relative AUC increasing with increasing dose. Therefore, the pharmacokinetic behavior of levodopa after oral administration to dogs and patients was dose dependent.

Dosage form design for improvement of bioavailability of levodopa II: bioavailability of marketed levodopa preparations in dogs and parkinsonian patients.

To estimate the absolute bioavailability of oral levodopa, plasma concentrations and urinary excretion of levodopa and its metabolites were determined in beagle dogs and in parkinsonian patients after intravenous and oral drug administration. The absolute bioavailability of orally administered levodopa was estimated to be about 35% in both dogs and patients; however, the total amount absorbed of intact drug and levodopa metabolites was estimated to be 80--90% of the administered dose. Due to the similarities of the pharmacokinetic characteristics of levodopa found in beagle dogs and in humans, beagle dogs can serve as a model to study bioavailability, absorption, and metabolic mechanisms.

Dosage form design for improvement of bioavailability of levodopa V: Absorption and metabolism of levodopa in intestinal segments of dogs.

Plasma levels of levodopa, total dopamine, and residual amounts of levodopa and its metabolites at the administered site were analyzed following administration of single 100-mg doses of levodopa in solution into isolated segments of the duodenum, jejunum, and ileum of the dog. The largest area under the plasma concentration-time curve (AUC) of levodopa during the 1.0-hr study was obtained following administration in the duodenum, followed by the jejunum and ileum. In addition, the residual amounts of levodopa and its metabolites detected at the administration sites were: ileum, 23%; jejunum, 7% and duodenum, less than 1%. The largest AUC of total dopamine was obtained following administration in the jejunum, followed by the ileum and duodenum. This order was consistent with the order of levodopa decarboxylase enzyme activity reported previously. Therefore, it can be concluded that the major absorption site of levodopa in the intestine resides in the upper small intestine. Levodopa in 10-, 50-, and 100-mg doses was administered into isolated duodenal segments. The AUC of levodopa increased nonlinearly with increasing dose. Negligible amounts of both levodopa and its metabolites were observed in the segment at 1.0 hr after administration, indicating that the duodenal absorption of levodopa was not saturable within the dose range tested.

Dosage form design for improvement of bioavailability of levodopa IV: Possible causes of low bioavailability of oral levodopa in dogs.

Several potential mechanisms for reduced levodopa bioavailability following oral administration to dogs and humans were investigated by studying the influence of the administration route on plasma levodopa levels after intravenous, hepatoportal, and duodenal administrations to dogs. The observed average areas under the plasma concentration-time curves (AUC) of levodopa following hepatoportal injection and intravenous injection were virtually identical; but following duodenal administration a decrease in the AUC of levodopa was observed with a concomitant increase in the AUC of total dopamine. The possible involvement of intestinal microorganisms in levodopa metabolism was explored in dogs that had been administered a combination of paromomycin and kanamycin to reduce intestinal microflora. Similar patterns of plasma level profiles and urinary excretion were observed between control and treated dogs. As measured by the release of [14C]carbon dioxide from [14C]levodopa, the distribution of levodopa decarboxylase enzyme activity in various parts of the intestine was studied in homogenates prepared from isolated intestinal segments of the duodenum and upper, middle, and lower parts of the jejunum and ileum. The jejunum showed the highest decarboxylase activity followed by the ileum and duodenum. These data indicate that the reduced bioavailability of orally administered levodopa occurs as a result of metabolism by levodopa decarboxylase enzyme in the gut wall.

Dosage form design for improvement of bioavailability of levodopa VI: formulation of effervescent enteric-coated tablets.

A new dosage form of levodopa, which has the characteristics of loading high concentrations of levodopa at the upper part of the intestine, has been developed to improve its bioavailability. It is shown that an effervescent tablet formulation, coated with hydroxypropyl methylcellulose phthalate (carboxybenzoyl radical content: 20-24%) as the enteric material, is suitable for the purpose of dissolution. This was confirmed from animal experiments, which showed that tablets of this composition disintegrate instantly on reaching the upper part of the intestine. This tablet was considered appropriate for the bioavailability tests described in this paper.

The bioavailability of flufenamic acid and its dissolution rate from capsules.

The bioavailabilities of five commercially available flufenamic acid (FA) capsules were studied in humans and beagle dogs. The dissolution rates of these capsules were determined by several methods. Experiments on in vitro/in vivo and humans/dogs correlations were performed to evaluate the dissolution test methods and the values of beagle dogs as models for predicting bioavailability of weak acid drugs in humans. Significant differences in the rates and extents of bioavailability of the different capsules were observed both in humans and dogs, but results in humans differed from those in dogs. The dissolution rates, determined by dissolution methods involving pretreatment with acidic solutions, correlated significantly with bioavailabilities in humans and dogs; however, those obtained by the rotating basket and paddle methods without any surface active agents did not correlate with in vivo data.