Characterizing the key determinants of variability in the exposure of orally administered drugs may be important in understanding the implications of exposure variability on clinical responses. In particular, partitioning overall variability into interoccasion variability (IOV) and interindividual variability (IIV) allows a better assessment of the clinical importance of exposure variability. The IOV characterizes the dose-to-dose variability in exposure within a subject and is likely to be less clinically relevant than IIV for chronically administered drugs as the effect of IOV averages out over repeated dosing. The main aims of this model-based analysis were (1) to characterize the IOV and IIV of dasatinib, a novel, orally administered, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases that is indicated for the treatment of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia and (2) to demonstrate using simulated data that it is possible to estimate IIV and IOV in relative bioavailability (F_R) of an orally administered drug, given an adequate sampling scheme. Variability in dasatinib exposure was estimated to be mainly due to IOV in F_R (44% coefficient of variation [CV]) and, to a lesser extent, due to IIV in F_R and IIV in clearance (32% and 25% CV, respectively). The IIV is expected to be more clinically relevant than IOV for chronically administered oral drugs such as dasatinib, as the overall variability in cumulative exposure will be mainly due to IIV. The analysis of simulated data demonstrated that models ignoring either IIV or IOV in F_R resulted in upwardly biased estimates of interindividual or residual variability. Thus, it may be important to account for both IIV and IOV in F_R, particularly for orally administered agents that exhibit absorption-related variability in exposure.

An approach for estimation of dosing strategies based on data-derived models and assessment of the risk associated with deviation from the treatment target is presented. The work is illustrated by establishing a dosing strategy to be used for a priori individualization on the basis of renal function for the antibiotic cefuroxime. Treatment involved exposing patients to concentrations above the minimum inhibitory concentration (MIC) for 50% of the dosing interval. The risk (penalty) function incorporated both deviations from the target and the use of excess amount of drug. Dosing strategies were estimated for a target population by minimizing the risk function. The population was characterized by a population pharmacokinetic model, and distributions of CLcr and body weight were reflective of the target group. The estimated dosing strategies were assessed by evaluating population distributions of (1) percentage of dosing interval with concentrations above MIC, (2) time of drug exposure below MIC, and (3) drug administered in excess to reach the target. These distributions were generated using wild-type MIC distributions for Escherichia coli and Streptococcus pneumoniae. The authors illustrate how benefits and risks of drug treatment can be weighed quantitatively in decision-based risk functions and subsequently used in the estimation of drug dosing.

The interindividual variability of tenofovir pharmacokinetics in HIV+ patients is quite large, but the sources of variability are incompletely understood. Intraindividual variability has not been characterized, although it may have an impact on efficacy and therapeutic drug monitoring. The aims of the study were to estimate intraindividual variability of tenofovir clearance and to assess interactions with associated antiviral drugs. Tenofovir concentrations (median 2; range, 1-5) were measured in 175 patients during several dosing intervals. Covariates and dosing regimen of associated antiretroviral drugs were recorded prospectively. The data were analyzed by a population approach. The final model was a 2-compartment model with first-order absorption rate. The elimination clearance was found to be related to the ratio of body weight to serum creatinine. Among the 15 drugs coadministered, no interaction on tenofovir kinetics was significant. The global variability of CL/F, after accounting for variability to variation of body weight and serum creatinine, was about 50%, with 20% due to interindividual variability and 30% due to interoccasion variability. In a few patients, clearance (and AUC) could vary by a factor of 2 between occasions. The interoccasion variability was not related to the delay between occasions. In the context of drug monitoring, for a given patient, the dose should not be adapted unless the variation of concentration between 2 occasions is large, or the 24-hour trough concentration at steady state is lower than 12 µg/L.

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C_max) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C_max were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C_max were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C_max were similar and formoterol AUC and C_max 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

The pharmacokinetics of amlodipine and olmesartan in healthy volunteers after coadministration of amlodipine besylate and olmesartan medoxomil concomitantly as separate dosage forms and together in a fixed-dose combination tablet were characterized in 5 phase I, randomized, crossover studies. The mean steady-state pharmacokinetics of amlodipine and olmesartan were similar when olmesartan medoxomil 40 mg/day and amlodipine 10 mg/day were administered separately or concomitantly for 10 days. The total and maximum exposure to amlodipine and olmesartan after administration of fixed-dose combination amlodipine/olmesartan medoxomil 10 mg/40 mg was bioequivalent to amlodipine 10 mg plus olmesartan medoxomil 40 mg. The ratio of least squares mean and 90% confidence intervals for the area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of amlodipine and olmesartan fell within the prespecified range for bioequivalence (80.0%-125.0%). The area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of both drugs also met the prespecified criterion for bioequivalence when the fixed-dose combination tablet was taken 30 minutes after a high-fat breakfast. Total exposure to amlodipine and olmesartan was dose-proportional after administration of olmesartan medoxomil 10 mg to 40 mg in the fixed-dose combination formulation with amlodipine 5 mg to 10 mg. From a pharmacokinetic perspective, the 2 drugs are well suited to coadministration in a fixed-dose combination.

This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K_m 2.1 µmol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K_m 72 µmol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC and C_max,ss of digoxin, atorvastatin, o-hydroxy-atorvastatin, and -hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.

Effects of single and multiple doses of oral ketoconazole on roflumilast and its active metabolite, roflumilast N-oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral roflumilast 500 µg once daily for 11 days and a concomitant 200-mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral roflumilast 500 µg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single-dose ketoconazole with steady-state roflumilast increased the AUC of roflumilast by 34%; C_max was unchanged. For roflumilast N-oxide, AUC and C_max decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C_max of roflumilast by 99% and 23%, respectively; for roflumilast N-oxide, AUC was unchanged, and C_max decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and roflumilast does not require dose adjustment of roflumilast.

The role of gender on the disposition of drugs metabolized by cytochrome P4503A (CYP3A) remains controversial. Some sources suggest that CYP3A activity in women exceeds that in men, but evidence to support this position is inconsistent at best. We evaluated 38 data sets in which clearance of CYP3A substrate drugs was studied in healthy young male and young female subjects. None of these drugs was a substrate for transport by P-glycoprotein (P-gp). The overall mean (±SE) for the female/male ratio of weight-normalized clearance was 1.26 (±0.07) for parenteral dosage and 1.17 (±0.07) for oral dosage. Both ratios were significantly different (P < .05) from 1.0. For oral dosage studies, the female/male clearance ratio was unrelated to the drug's absolute oral bioavailability. Thus gender has a small and statistically significant, although most likely clinically unimportant, influence on CYP3A phenotype for substrates not transported by P-gp.

The primary objective was to determine the pharmacokinetics of single oral and intravenous doses of pantoprazole in children 2 to 16 years of age. The secondary objective was to assess the safety and tolerability of these doses. Male and female hospitalized and nonhospitalized patients from ages 5 to 16 years received single oral doses (20 mg or 40 mg), and those from ages 2 to 16 years received single intravenous doses (0.8 mg/kg or 1.6 mg/kg) of pantoprazole. The plasma concentration-time data for each patient were analyzed using noncompartmental methods. Routine safety and tolerability assessments were also obtained. The mean values for peak plasma concentration and total area under the plasma concentration-time curve increased with increasing dose. Pharmacokinetic values were similar in patients from ages 2 to 16 years and to those previously obtained in adults. Statistically significant differences were observed for dose-normalized pantoprazole area under the plasma concentration-time curve when compared between CYP2C19 extensive metabolizers with 1 versus 2 functional alleles. All adverse events were mild in severity and considered to be unrelated to study drug. The pharmacokinetic profile of oral and intravenous pantoprazole was similar in children ages 2 to 16 years. The doses used here were safe and well tolerated in this population.