Exploring clinical study design by computer simulation based on pharmacokinetic/pharmacodynamic modelling.

Computer simulations have been successfully applied in various industries (e.g. automobile, aerospace) to make product development more efficient. Just recently, it was suggested to use simulations in support of clinical drug development for predicting clinical outcomes of planned trials. The methodological basis for this approach is provided by pharmacokinetic and pharmacodynamic mathematical models together with Monte Carlo techniques. In the present paper, the basic notions of clinical trial simulation are introduced and illustrated with the example of an oral anticancer drug. It is shown that computer simulation helps to evaluate consequences of design features on safety and efficacy assessment of the drug which are not easily obtained otherwise. An overview of existing simulation resources with respect to training and software is provided.

An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche.

The integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the 'pharmacokinetic-pharmacodynamic guided approach to drug development'. The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach. This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development. (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase II or III studies. In 4 projects, 1 clinical study was avoided. (iii) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects). The results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.

Factors influencing elimination and distribution of fleroxacin: metaanalysis of individual data from 10 pharmacokinetic studies.

A metaanalysis was conducted on data from 172 subjects (healthy volunteers and uninfected patients) included in 10 pharmacokinetic studies of fleroxacin after oral administration. The objectives of this analysis were (i) to estimate the typical values of two key pharmacokinetic parameters, clearance over systemic availability (CL/F) and volume of distribution over systemic availability (V/F), after the administration of therapeutic doses and (ii) to study qualitatively and quantitatively the factors which influence the elimination and distribution of fleroxacin. The main pharmacokinetic parameters, CL/F and V/F, were analyzed separately by a standard two-stage approach. The covariates investigated were predicted creatinine clearance (CLCR), age, gender, body surface area, body weight, and lean body weight (LBW). The predicted CL/F and V/F were 83.5 ml/min and 101 liters, respectively, for a typical male subject (CLCR, 70 ml/min; LBW, 54 kg; age, 54 years). Modeling of CL/F indicated that this parameter increases linearly with CLCR, decreases linearly with age, and is 10.8 ml/min lower in females than in males. The best model for V/F showed a linear increase with LBW and a linear decrease with age. V/F was found to be 20.4 liters greater in males than in females. In conclusion, this metaanalysis has shown that CLCR, age, and gender influence the elimination of fleroxacin from the body, whereas V/F is influenced by LBW, age, and gender.

Pentachlorophenol carcinogenicity: extrapolation of risk from mice to humans.

1. Pentachlorophenol (PCP) has been found to be carcinogenic in mice. The objective of this study was to extrapolate to humans the risk of cancer from data obtained in mice using information on disposition, serum protein binding and metabolism of PCP across species. 2. A review of the literature indicates that neither PCP nor a mutagenic metabolite, tetrachlorohydroquinone (TCHQ), has been specifically identified as responsible for the carcinogenicity. In addition, the occurrence of TCHQ as a metabolite of PCP in humans is still questionable. Therefore, cancer risk assessment is performed on the assumption that PCP itself is responsible for the carcinogenicity. 3. For interspecies extrapolation, a new method in which interspecies differences in clearance and serum protein binding are taken into account is used. The method gives estimates of equivalent human doses of PCP which are up to 4 times smaller than those obtained using body surface area. For both interspecies extrapolation methods, the estimated virtually-safe doses of PCP are smaller than the average daily intakes reported in groups of subjects nonspecifically exposed to PCP. Corresponding extra risks of cancer for lifetime exposure are from 20 to 140 times greater than the acceptable extra risk (10(-6)). The results obtained with this approach indicate that PCP is a possible public health hazard.

Pharmacokinetic concepts in assessing intake of pentachlorophenol by rats after exposure through drinking water.

The objective of this study was to predict concentrations of a toxicant in plasma after exposure to the toxicant through drinking water using basic pharmacokinetic principles. As an example, we studied pentachlorophenol (PCP), a widely used wood preservative of public health concern as an environmental pollutant. We added PCP to the drinking water (30 micrograms/mL) of five rats for 3 days. Blood was sampled, and water consumption was monitored every 12 h on the days 1 and 2 and every 3 h on day 3. After a 4-day washout, a PCP dose of 2.5 mg/kg was given intravenously, and blood was withdrawn at selected times for 2 days. PCP concentrations in plasma were measured by capillary gas chromatography. A one-compartment model with zero-order input and kinetic parameters (clearance, volume of distribution, and bioavailability) estimated after intravenous administration adequately predicted PCP concentrations in plasma during exposure to PCP. The average steady-state concentration (Css), which reflects the overall exposure, was predicted using the clearance (CL) concept [i.e., Css = (bioavailability.rate of intake)/CL] and compared with the observed value. The data for PCP demonstrate the potential utility of CL and other kinetic concepts in assessing exposure to a toxicant in drinking water, food, or air.

Disposition, bioavailability, and serum protein binding of pentachlorophenol in the B6C3F1 mouse.

The toxicokinetics of pentachlorophenol (PCP) were studied in B6C3F1 mice, a strain in which PCP was previously found to be carcinogenic. In a crossover design, doses of 15 mg/kg were given intravenously (bolus) and orally (gastric intubation) to six animals. Concentrations of PCP in blood, urine, and feces were measured by capillary gas chromatography with electron-capture detection. After intravenous administration, the values of clearance and volume of distribution were 0.057 +/- 0.007 L/hr/kg and 0.43 +/- 0.06 L/kg, respectively. These two parameters exhibited low intermouse variability (coefficients of variation less than 14%). The elimination half-life was 5.2 +/- 0.6 hr. After oral administration, the PCP peak plasma concentration (28 +/- 7 micrograms/ml) occurred at 1.5 +/- 0.5 hr and absorption was complete (bioavailability = 1.06 +/- 0.09). The elimination half-life was 5.8 +/- 0.6 hr. Only 8% of the PCP dose was excreted unchanged by the kidney. PCP was primarily recovered in urine as conjugates. A portion of the dose was recovered in urine as the mutagen, tetrachlorohydroquinone (5%) (TCHQ), and its conjugates (15%). For both PCP and TCHQ, sulfates accounted for 90% or more of the total conjugates (glucuronides and sulfates).

Assessment of pentachlorophenol exposure in humans using the clearance concept.

1. Pentachlorophenol (PeCP), a widely-used wood preservative, is a ubiquitous compound which has been found to be carcinogenic in mice. The objective of this study is to assess the average net daily intake of PeCP in cohorts of individuals who are: (1) not specifically exposed to PeCP, (2) residents of homes made of PeCP-treated logs and (3) occupationally exposed to PeCP. 2. The average net daily intake was calculated using a basic pharmacokinetic principle, the clearance (CL) concept: net daily intake equals CL (in 1 d-1) times the average steady-state concentration of PeCP in plasma (Css). Css values reported in the literature were used for the calculations. 3. Because the two definitive studies on PeCP toxicokinetics in humans have given conflicting results, kinetic information from human exposure to PeCP was reviewed. Plasma clearance was estimated from retrospective analysis of urine and plasma concentrations measured in people after long-term exposure to PeCP. An overall clearance of 0.425 l d-1 was obtained. 4. In groups of individuals who are not specifically exposed to PeCP, net daily intake estimated in eight countries varied from 5 micrograms (Nigeria) to 37 micrograms (The Netherlands). Net intake was between 51 micrograms d-1 and 157 micrograms d-1 in residents of homes made of PeCP-treated logs. In individuals occupationally exposed to PeCP, net daily intake varied widely (from 35 micrograms to about 24,000 micrograms) depending on the type of work.

Pentachlorophenol toxicokinetics after intravenous and oral administration to rat.

1. The toxicokinetics of pentachlorophenol (PCP) were studied in rats. Doses of 2.5 mg/kg were given i.v. (bolus, five rats) and orally (gastric intubation, five rats). Concentrations in plasma, urine and faeces were measured by capillary g.l.c. with electron-capture detection. 2. After i.v. administration, the clearance and volume of distribution at steady state were 0.026 +/- 0.003 l/h per kg and 0.25 +/- 0.02 l/kg, respectively. These two parameters exhibit low inter-rat variability (coefficients of variation less than 15%). The half-life of the initial decline of PCP plasma concn. was less than 1.3 h, while the second phase half-life was 7.11 +/- 0.87 h. 3. After oral administration the peak plasma concn. (7.3 +/- 2.8 micrograms/ml) occurred between 1.5 and 2 h and absorption was complete (bioavailability = 0.91-0.97). No distinct distribution phase was observed and the elimination half-life was 7.54 +/- 0.44 h. 4. PCP clearance is essentially metabolic since only 5.3 +/- 0.2% dose is eliminated unchanged by the kidney. About 60% dose was recovered in urine, mainly as conjugated PCP and conjugated tetrachlorohydroquinone (TCHQ). 5. For both routes of administration, about 10% dose was recovered in faeces as PCP and/or metabolites, which indicates that biliary excretion contributes to total elimination.

Theoretical model for both saturable rate and extent of absorption: simulations of cefatrizine data.

A pharmacokinetic model incorporating saturable rate of absorption of the Michaelis-Menten type was recently developed to fit cefatrizine (CFZ) plasma concentrations with time following oral administration of 500-mg capsules to humans. This model (MM) was statistically superior to models incorporating either first-order or zero-order absorption. However, the MM model does not predict the reduction in extent of absorption with dose observed in vivo. In this study, a model is proposed in which a time constraint, delta t, is added to the MM model. This new model (MM-delta t) is tested with data following doses of 250, 500, and 1000 mg of CFZ. When delta t is set to 1.5 hr, the predicted relative changes with dose in bioavailability, F, peak plasma concentration, Cmax, the time at which the peak concentration occurs tmax, and the mean absorption time, MAT, are generally in good agreement with the experimental data. The time interval of 1.5 hr is compatible with passage by a limited region within the small intestine where drug is absorbed by a facilitated transport mechanism. Influence of each absorption model parameter (Vmax, Km, and delta t) on total area under the concentration versus time curve (AUC), F, Cmax, and tmax, is assessed by simulation. The MM-delta t model is able to summarize the nonlinerity observed in both rate and extent of absorption.

Simultaneous assay of pentachlorophenol and its metabolite, tetrachlorohydroquinone, by gas chromatography without derivatization.

A sensitive capillary gas chromatographic method was developed for the simultaneous determination of pentachlorophenol and its major metabolite, tetrachlorohydroquinone, in plasma, urine and feces. The method involved a simple one-step liquid-liquid extraction with diethyl ether and electron-capture detection gas chromatography on a fused-silica capillary column coated with 50% methylsilicone-50% trifluoropropylsilicone. The detection limit of both compounds was 50 ng/ml in plasma (from an initial volume of 0.1 ml), 100 ng/ml in urine and 100 ng/g in feces. Optimal conditions for both chemical and enzymatic hydrolysis were defined to measure conjugates of both pentachlorophenol and tetrachlorohydroquinone in urine. Tetrachlorohydroquinone was found to be unstable in plasma and urine; means to prevent its degradation during sample collection and storage by addition of ascorbic acid and ethylenediaminetetracetic acid are presented. This chromatographic method was shown to be precise, accurate and specific. It was successfully applied to toxicokinetic studies in rat.

[Pharmacokinetics of ponsinomycine with repeated ingestion in healthy volunteers]. / Pharmacocinétique de la ponsinomycine administrée en prises répétées chez le volontaire sain.

Ponsinomycin or miocamycin (MOM) is a new macrolide which is totally metabolized in vivo. The disposition of its 3 major metabolites (Mb12, Mb6 and Mb9a), was investigated following multiple dosing with ponsinomycin at a dose of 800 mg every 12 h, for 8 days, in healthy volunteers. Drug measurements were conducted by high performance liquid chromatography. In agreement with the low values of their apparent elimination half-lives, respectively less than 1.5 h and 3.0 h, metabolites Mb12 and Mb9a did not accumulate with time. Their pharmacokinetics was apparently stable with time. Conversely Mb6 did accumulate, by approximatively a factor 2, although its apparent elimination half-life was only close to 2 h. This value must therefore be considered with caution. A dose dependency effect was previously observed, Mb6 pharmacokinetics could be non linear with time as well. The relative importance of this metabolite is therefore greater at steady-state, following multiple administration than after single dosing with ponsinomycin.

Saturable rate of cefatrizine absorption after oral administration to humans.

This study examined the absorption kinetics of cefatrizine, an amino-beta-lactam antibiotic, after oral administration of a single 500-mg dose to 12 healthy volunteers. Plasma concentrations were determined by high performance liquid chromatography. The plots of the percentage of drug unabsorbed and the apparent rate of cefatrizine absorption as a function of time showed, first, a delay and, then, an almost constant rate of absorption with a tendency to move toward first-order kinetics at the end of the process. Three compartmental models incorporating a lag time and first-order elimination kinetics, but differing in their input rate, were used for analysis of the time course of cefatrizine plasma concentrations. The model with first-order absorption kinetics was clearly inadequate. The results were improved with the model for which the rate of absorption is constant, but a model incorporating saturable absorption kinetics of the Michaelis-Menten type improved the fit further. This last model was statistically superior to the constant-rate input model in 6 out of 12 subjects, according to the likelihood-ratio method. Because of the innovative feature of the model incorporating the Michaelis-Menten equation, simulations of the effect of altering the model parameters and the dose administered on the concentration-time profile, were performed. Different hypotheses which might explain why cefatrizine absorption kinetics fits the Michaelis-Menten equation were examined. The observation of saturable absorption kinetics is consistent with a carrier-mediated transport previously reported to occur in the gastrointestinal tract of rats.

Steady-state bioavailability and pharmacokinetics of ambroxol and clenbuterol administered alone and combined in a new oral formulation.

Ambroxol and clenbuterol are two drugs with potential pharmacological synergy. The objective of this study was to compare the apparent bioavailabilities at steady-state of these two compounds administered alone or in combination (CHF-023). Nine healthy male volunteers participated in the study. They received 30 mg of ambroxol alone (one Fluibron tablet), or 20 micrograms of clenbuterol alone (one Spiropent tablet), or 30 mg of ambroxol plus 20 micrograms of clenbuterol in combination (one CHF-023 tablet), every 12 hours for 7 days on three separate occasions. Ambroxol and clenbuterol concentrations were measured in plasma by appropriate GC/MS methods. Pharmacokinetic parameters were calculated by non-compartmental methods and submitted to statistical comparisons. Compartmental analysis was also performed on data provided by CHF-023 treatment. It was concluded that apparent bioavailabilities of ambroxol and clenbuterol are almost identical in Fluibron and CHF-023 tablets, and in Spiropent and CHF-023 tablets, respectively, with no statistically significant differences between pharmacokinetic parameters calculated for these two drugs during different treatments, except for peak concentration of ambroxol.

[Pharmacokinetics of cefatrizine administered in repeated doses]. / Pharmacocinétique de la céfatrizine administrée en doses répétées.

Twelve healthy volunteers received cefatrizine orally at doses equal to 500 mg every 12 h for 5 days. Cefatrizine was assayed by high performance liquid chromatography in plasma and urines collected after the first and/or the last administration. Cefatrizine absorption was rapid; its peak plasma level was reached at time 1.79 +/- 0.07 h following the first dose, it was equal to 7.37 +/- 0.31 micrograms.ml-1. Its apparent elimination half-life was equal to 1.50 +/- 0.05 h, it explains the lack of accumulation with time during multiple administrations every 12 hours. Comparisons between peak plasma concentration and area under curves following the first and last dosing showed significant (p less than 0.01) but weak (close to 15%) reduction of these 2 parameters with time which could be explained by a slight reduction of cefatrizine absorption with time. In conclusion, cefatrizine does not accumulate when administered repeatedly at a dose equal to 500 mg every 12 h in young adult, and its pharmacokinetics is virtually linear with time.