Guoliang Cao

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir*

To assess the pharmacokinetic interaction between ritonavir and saquinavir.

Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy

The availability of an intravenous formulation now makes possible rapid administration of valproate (VPA) loading doses, but estimates of key VPA pharmacokinetic parameters in patients have limited the use of this approach. VPA disposition was characterized in 112 epilepsy patients, with or without enzyme inducing comedications, randomized to either 3.0 or 1.5mg/kg/min infusions of valproate sodium injection. Maximum dose was </=15mg/kg per infusion. Total and unbound plasma VPA concentrations were determined from blood samples obtained prior to and for 6h following the infusion. Analyses of covariance assessed the effect of induction, weight, age, gender, albumin, creatinine, and infusion rate on pharmacokinetics. Maximum total and unbound VPA concentrations were 94 and 14mg/l, respectively. Total concentration fell below 50mg/l within 3h in induced and 6h in uninduced patients. VPA unbound fraction decreased from 15% at maximum concentration to 9% at 45mg/l. The mean (S.D.) distribution volume was 0.21 (0.044)l/kg. Induction status, albumin concentration, and infusion rate significantly affected pharmacokinetics. Measurement of unbound VPA may be useful when alterations in binding are suspected. Infusions up to 3mg/kg/min produce predictable total VPA concentrations when induction status and albumin levels are considered.

Pharmacokinetics of sertindole in healthy young and elderly male and female subjects

The pharmacokinetic disposition of oral sertindole, a new selective antipsychotic compound, in young and elderly male and female subjects was investigated.

The pharmacokinetic and pharmacodynamic interaction between zileuton and terfenadine.

AbstractObjectives: The effects of zileuton on terfenadine pharmacokinetics, and the effects of terfenadine alone and the combination on the duration of the QTc interval and the morphology of the TU complex were examined. Methods: The study was double-blind, randomized, placebo-controlled, two period cross-over in 16 healthy volunteers. During each period, subjects received 60 mg of terfenadine every 12 h on days 1 to 7 and 600 mg of either zileuton or placebo for zileuton every 6 h on days 1 to 10. Blood samples were obtained on days 7 to 10 and serial ECGs were performed on days –1 and 7 in both periods. Results: The combination of zileuton and terfenadine was well tolerated. Coadministration of zileuton with terfenadine resulted in a significant increase in the mean AUC and Cmax of terfenadine by approximately 35% and the mean AUC and Cmax of carboxyterfenadine by approximately 15%. The maximum concentration of terfenadine observed in the study was 9.6 ng · ml−1. The addition of zileuton to terfenadine did not result in significant changes in the evaluated ECG-recordings (QTc interval and morphology of TU complex). The difference in means for both maximum and average QTc interval was very small (≤ 2.3 ms), and there were no clinically significant changes in individual values. Conclusions: The relatively small pharmacokinetic effect of zileuton on terfenadine metabolism, with no change in the QTc interval, is unlikely to be of clinical significance. The interaction is minimal in comparison to the background variability of the population.

Population analysis of the pharmacokinetics and pharmacodynamics of seratrodast in patients with mild to moderate asthma

Seratrodast, a potent thromboxane receptor antagonist, is approved in Japan for the treatment of asthma and currently is being developed in the United States.

The effect of erythromycin on the CYP3A component of sertindole clearance in healthy volunteers.

The effect of erythromycin on the pharmacokinetic disposition of oral sertindole, a new antipsychotic compound, was investigated. Ten subjects who completed the study received a single 4‐mg dose of sertindole without or with concomitant erythromycin 250 mg taken orally 4 times daily. Coadministration of sertindole and erythromycin led to a 33% decrease (P < 0.05) in mean (±SD) time to reach maximum plasma concentration (tmax) value and a 15% elevation (P < 0.05) in the mean maximum plasma concentration (Cmax) value of sertindole. The mean area under the concentration—time curve (AUC) value of sertindole did not change significantly in the presence of erythromycin (alone: 159 ± 111 ng.hr/mL, in combination: 179 ± 144 ng.hr/mL, P >0.05). The presence of erythromycin also significantly increased the dehydrosertindole Cmax and AUC means by 16% and 21%, respectively, possibly due to inhibition of the CYP3A metabolic isozyme responsible for the elimination of this metabolite. The rate of absorption of sertindole and the rate of appearance of dehydrosertindole in the systemic circulation after a 4‐mg sertindole single dose were slightly enhanced by concomitant dosing of erythromycin. In conclusion, there is a small but noticeable effect of erythromycin on the pharmacokinetic disposition of sertindole. The effects are believed to have little clinical significance.

Assessing Whether Controlled Release Products with Differing in Vitro Dissolution Rates Have the Same in Vivo-in Vitro Relationship

In order to demonstrate a complete in vivo-in vitro correlation (IVIVC) for a controlled release (CR) formulation, it is necessary that the relationship between in vivo percent absorbed and in vitro percent dissolved be the same whether the dissolution rate is as targeted or whether the dissolution rate is faster or slower than intended for the marketed product. This is essential if the IVIVC will be used in the future for a decision on the acceptability of a change in the formulation. Suppose that a four period cross-over study is performed, with each subject receiving the to-be-marketed CR product, a product with a faster in vitro dissolution rate, a product with a slower dissolution rate, and an intravenous dose (or perhaps an oral dose of an immediate release formulation). Using an appropriate deconvolution method, for each subject and each CR product the percent absorbed is estimated for each time post dose for which the in vitro percent dissolved is measured. We present a method for the assessment of whether the relationship between in vivo percent absorbed and in vitro percent dissolved is the same for the three CR products

The Pharmacokinetic/Pharmacodynamic Interaction Between Zileuton and Terfenadine

Clinical Pharmacology & Therapeutics (1996) 59, 203–203; doi: 10.1038/sj.clpt.1996.311