Model-based drug development.

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.

Quantitative assessment of exposure-response relationships for the efficacy and tolerability of varenicline for smoking cessation.

Population exposure-response analyses involving approximately 2,000 cigarette smokers provided an integrated understanding of dose, exposure, patient characteristics, and response relating to the efficacy and tolerability of varenicline for smoking cessation. Full models with a linear function of area under the concentration-time curve at steady state AUC(0-24)(ss) and covariate effects on the baseline probability of response were constructed. Logistic regression results consistently showed that the end-of-treatment abstinence rate increased with increasing varenicline exposure, from 38% at 0.5 mg b.i.d. to 56% at 1 mg b.i.d. (vs. 22% for placebo). Baseline smoking status and age were predictive of smoking cessation, whereas race and gender showed little or no influence. Nausea was the most common adverse event, with an incidence that was gender-related and that increased with varenicline exposure; at a dosage of 1 mg b.i.d. the predicted probability of nausea relative to placebo was 24 vs. 7% in male subjects and 40 vs. 14% in female subjects. The incidence of nausea also showed a decreasing trend with time.

A novel quantitative method for determining the biodistribution of radiolabeled xenobiotics using whole-body cryosectioning and autoradioluminography.

A novel method is described for quantitative whole-body autoradioluminography using [14C]-radioactive standards prepared from rat red blood cells. MicroComputer Imaging Device model 2 (MCID) and ImageQuant (IQ) imaging systems were evaluated for imaging performance and autoradioluminography quantitation. Weighted linear regression analysis resulted in linearity over five orders of magnitude with a lower limit of quantitation of 2.7 nCi/g. Using IQ, 16 days were necessary for image analysis and data processing of 30 whole-body cryosections and 1080 standards. MCID reduced the image and data processing of the same cryosections and standards to only 4 days. Embedding a series of radioactive standards with each specimen in the same carboxymethyl cellulose block provided an effective method of assessing intrasection and intersection variations in thickness of whole-body cryosections. These results demonstrated that autoradioluminography provided a sensitive, accurate, precise and reproducible method for the quantitative measurement of the tissue distribution of [14C]-radiolabeled xenobiotics in whole-body cryosections. Evaluating the biodistribution of [14C]-xenobiotics by autoradioluminography, not only provides pharmacokinetic data required for predicting the potential tissue deposition of an absorbed dose of radioactivity in man, but also allows for visual and quantitative evaluation of radioactivity in small anatomical structures that otherwise could not be detected or measured by conventional tissue combustion technology.

Determination of trovafloxacin, a new quinolone antibiotic, in biological samples by reversed-phase high-performance liquid chromatography.

A simple, accurate and precise high-performance liquid chromatographic method was developed and validated for the determination of trovafloxacin, a new quinolone antibiotic, in serum and urine. Following solid-phase extraction, chromatographic separation was accomplished using a C18 column with a mobile phase consisting of 0.04 M H3PO4-acetonitrile-tetrabutylammonium hydroxide-0.005 M dibutyl amine phosphate (D-4) reagent (83:16.85:0.05:0.1, v/v), pH 3. Trovafloxacin and the internal standard (a methyl derivative of trovafloxacin) were detected by ultraviolet absorbance at 275 nm. The lower limit of quantification for trovafloxacin was 0.1 microgram/ml and the calibration curves were linear over a concentration range of 0.1 to 20.0 micrograms/ml (r2 = 0.9997). The average recoveries were greater than 70% for both trovafloxacin and internal standard. The intra-day and inter-day coefficients of variation were generally less than 5% in urine and serum over the concentration range of 0.1 to 20.0 micrograms/ml. Human serum samples could be stored for up to 12 months at -20 degrees C and urine samples could be stored up to 18 months at -80 degrees C.

The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium.

AIMS: To assess the potential of ziprasidone to alter the renal clearance and steady-state serum levels of lithium. METHODS: Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day(-1), given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day(-1), given as two divided daily doses, on days 9-11 followed by 80 mg day(-1), given as two divided daily doses on days 12-15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium. RESULTS: Ziprasidone administration was associated with a 0.07 mmol l(-1) (13%) mean increase in steady-state serum lithium levels compared with a mean increase of 0.06 mmol l(-1) (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h(-1) (5%) in the ziprasidone group and by 0.14 l h(-1) (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant. CONCLUSIONS: Ziprasidone does not alter steady-state serum lithium concentrations or renal clearance of lithium.

Single- and multiple-dose pharmacokinetics of ziprasidone in healthy young and elderly volunteers.

AIMS: To compare the pharmacokinetics of ziprasidone in healthy young (18-45 years) men and women, and healthy elderly (> or = 65 years) men and women. METHODS: Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1-8, for up to 12 h after dosing on day 1 and for up to 96 h after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group. RESULTS: Steady-state serum concentrations of ziprasidone were achieved within 2-3 days. The steady-state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs. 69 ng ml(-1) and tmax (3.19 vs. 4.81 h) but no differences in AUC(0,12 h) or lambda(z). Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 h) (560 vs. 465 ng ml(-1) h), Cmax (85 vs. 69 ng ml(-1) and lambda(z) (0.126 vs. 0.197 l h(-1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 h, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large. CONCLUSIONS: The influence of age and gender on the pharmacokinetics of ziprasidone is not clinically significant.