A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

Simplification of Imipenem Dosing by Removal of Weight-Based Adjustments.

In patients with renal insufficiency, dose adjustments based on creatinine clearance and body weight have been a component of imipenem dosage instructions. The objective of the current analysis was to provide revised dosing recommendations by evaluating the impact of creatinine clearance and body weight on the pharmacokinetics of imipenem. A population pharmacokinetics model was developed with data from 465 patients and 3300 pharmacokinetic samples. Simulations provided data to support revision of the dosing recommendations to remove body weight-adjusted dosing, and the analysis formed the basis for updates that are reflected on the current imipenem label for both the United States and Europe. The optimized regimen provided an advantage in terms of improved target attainment at breakpoint minimum inhibitory concentration values of 1 and 2 µg/mL, as low-body-weight patients maintained >90% probability of target attainment compared to <90% probability of target attainment achieved with the previously approved regimen. It was concluded that additional dose adjustments for body weight were not necessary and the new scheme would simplify dosing while maintaining patient safety and efficacy.

Pharmacokinetics and Tolerability of Letermovir Coadministered With Azole Antifungals (Posaconazole or Voriconazole) in Healthy Subjects.

Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions.

Insulin glargine and its two active metabolites: A sensitive (16pM) and robust simultaneous hybrid assay coupling immunoaffinity purification with LC-MS/MS to support biosimilar clinical studies.

MK-1293 is a newly approved follow-on/biosimilar insulin glargine for the treatment of Type 1 and Type 2 diabetics. To support pivotal clinical studies during biosimilar evaluation, a sensitive, specific and robust liquid chromatography and tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantification of glargine and its two active metabolites, M1 and M2 were developed. Strategies to overcome analytical challenges, so as to optimize assay sensitivity and improve ruggedness, were evolved, resulting in a fully validated LC-MS/MS method with a lower limit of quantification (LLOQ) at 0.1ng/mL (∼16pM, equivalent to ∼2.8µU/mL) for glargine, M1 and M2, respectively, using 0.5mL of human plasma. The assay employed hybrid methodology that combined immunoaffinity purification and reversed-phase chromatography followed by electrospray-MS/MS detection operated under positive ionization mode. Stable-isotope labeled 6[D10]Leu-glargine and 4[D10]Leu-M1 were used as internal standards. With a calibration range from 0.1 to 10ng/mL, the intra-run precision (n=5) and accuracy were <6.21%, and 96.9-102.1%, while the inter-run (n=5/run for 7days) precision and accuracy were <9.55% and 96.5-105.1%, respectively, for all 3 analytes. Matrix effect, recovery, analyte stability, and interferences from control matrix, potential concomitant medications and anti-drug antibody were assessed. The assay was fully automated and has been successfully used in support of biosimilar clinical studies. Greater than 94.3% of incurred sample reanalysis (ISR) results met acceptance criteria, demonstrating the robustness of the assay. The strategic considerations during method development and validation are discussed, and can be applied to quantification of other peptides, especially insulin analogs, in the future.

Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone.

PURPOSE: To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone. METHODS: This was an open-label, two-period, two-treatment, fixed-sequence study in 18 healthy subjects. On Day 1, Period 1, subjects received a single dose of rosiglitazone 8 mg. In Period 2, subjects received vorapaxar 40 mg on Day 1, vorapaxar 7.5 mg once-daily on Days 2-7, and a single dose of rosiglitazone 8 mg on Day 7. Rosiglitazone and N-desmethylrosiglitazone pharmacokinetics were assessed alone (Period 1) and after coadministration with vorapaxar (Period 2). Vorapaxar and its M20 metabolite pharmacokinetics were assessed on Day 7, Period 2. Safety and tolerability were assessed throughout the study. RESULTS: Coadministration of rosiglitazone with vorapaxar had no effect on rosiglitazone or N-desmethylrosiglitazone pharmacokinetics. The ratio of geometric means (GMR) and 90% confidence intervals (CI) of the coadministration versus monotherapy for Cmax (GMR 95; 90% CI 88, 103) and AUC0-24 h (GMR 103; 90% CI 98, 108) were within the 80-125% bioequivalence criteria. The metabolite-to-parent exposure ratio with and without vorapaxar was unaltered. Coadministration of vorapaxar with rosiglitazone was generally well tolerated. CONCLUSION: Coadministration of vorapaxar with rosiglitazone or drugs metabolized via CYP2C8 is unlikely to cause a significant pharmacokinetic interaction.

Exploring the influence of renal dysfunction on the pharmacokinetics of ribavirin after oral and intravenous dosing.

Although ribavirin is minimally cleared by renal elimination, its pharmacokinetics are substantially altered in patients with chronic renal impairment. This open-label study assessed the pharmacokinetics of single 400-mg oral and intravenous (IV) doses of ribavirin in two healthy volunteers and 12 patients with varying degrees of chronic renal impairment. Blood and urine samples were collected pre-dose and up to 168 h post-dose for pharmacokinetic analyses. Ribavirin area under the plasma concentration-time curve from time zero to time of final quantifiable sample and maximum plasma concentration values were increased, and total plasma clearance (CL), renal clearance (CLr), non-renal clearance (CLnr), volume of distribution at steady state (Vdss), and amount excreted values were reduced in patients with renal dysfunction compared with those who had normal renal function. Following IV administration, mean CLr was 54%, 23%, and 10% in patients with mild, moderate, and severe renal dysfunction, respectively, relative to control subjects, and was 56%, 28%, and 9% of control values after oral dosing. After IV dosing, mean CLnr was 94%, 76%, and 75% of control values in patients with mild, moderate, and severe renal dysfunction, respectively, and was 54%, 48%, and 27% of control values after oral dosing. Mean oral bioavailability of ribavirin was 35%, 60%, 57%, and 71% in control subjects and patients with mild, moderate, and severe renal dysfunction, respectively. These data indicate that there are multiple mechanisms (increased oral bioavailability, reduced CLr and CLnr, reduced Vd) contributing to altered ribavirin pharmacokinetics in chronic renal impairment.

Evaluation of potential for pharmacokinetic interaction between mometasone furoate and formoterol fumarate after oral inhalation from a fixed-dose combination metered-dose inhaler device.

A fixed-dose combination (FDC) containing mometasone furoate (MF) and formoterol fumarate (F) in a pressurized metered dose inhaler (MDI) is approved for asthma and is being developed for COPD. This randomized, open-label, 4-period crossover study compared single-dose pharmacokinetics of MF 800 µg; F 20 µg; MF 800 µg + F 20 µg coadministered (MF + F); and MF 800 µg/F 20 µg (MF/F) FDC in healthy subjects. MF, F, and MF + F were administered from single-ingredient MDI devices. MF and formoterol plasma samples were obtained predose and up to 48 hours post dose for estimation of AUC0-tf (primary endpoint) and Cmax . Treatments were deemed comparable if the 90% CIs for the geometric mean ratios (GMRs) fell within 70-143%. MF AUC0-tf was comparable following treatment with MF + F versus MF (GMR 98%; 90% CI 85-113%) and MF/F versus MF + F (GMR 95%; 90% CI 82-109%). Similarly, formoterol AUC0-tf was comparable following treatment with MF + F versus F (GMR 98%; 90% CI 77-124%) and MF/F versus MF + F (GMR 108%; 90% CI 85-136%). The 90% CIs for MF and formoterol Cmax fell within the prespecified comparability bounds for all comparisons. Systemic exposures to MF and formoterol were similar following treatment with the FDC MDI device versus individual or concomitant use of single-ingredient MDI devices.

An evaluation of the systemic bioavailability of mometasone furoate (MF) after oral inhalation from a MF/formoterol fumarate metered-dose inhaler versus an MF dry-powder inhaler in healthy subjects.

PURPOSE: This randomized, open-label, multiple-dose, two-period, crossover study compared the systemic bioavailability of mometasone furoate (MF) administered from a metered-dose inhaler containing MF and formoterol fumarate (F) (MF/F-MDI) versus MF administered from a single-ingredient dry-powder inhaler (MF-DPI). METHODS: Healthy, non-smoking adults, 18-65 years with body mass index 18-29 kg/m(2) (N = 12) received MF 800 µg/F 20 µg via MF/F-MDI or MF 800 µg via MF-DPI twice daily for 5 days separated by a 7-day period. MF pharmacokinetics (AUC(0-12 hour) , Cmax , and Tmax ) were measured at Day 1 and 5 after each treatment. Safety and tolerability were assessed. RESULTS: Systemic exposure to MF based on AUC(0-12 hour) was ∼25% lower following MDI versus DPI administration. The Day 5 geometric mean ratio (MDI/DPI) estimates (90% confidence intervals [CI]) for AUC(0-12 hour) and Cmax were 0.747 (0.61, 0.91) and 0.606 (0.49, 0.75), respectively. The accumulation index (R) value for MF was higher following MDI (3.81-fold) versus DPI administration (2.34-fold) indicative of prolonged absorption. The most common adverse events were tremor, headache, and catheter site pain. CONCLUSIONS: Systemic exposure to MF was lower following multiple-dose MF/F-MDI administration versus MF-DPI administration. The magnitude of this difference is not considered to be clinically important. MF/F-MDI was safe and generally well tolerated.

Hypothalamic-pituitary-adrenal axis effects of mometasone furoate/formoterol fumarate vs fluticasone propionate/salmeterol administered through metered-dose inhaler.

BACKGROUND: The effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products. METHODS: In a randomized, open-label, placebo-controlled, parallel group study, 66 patients with mild to moderate asthma received one of the following four treatments bid through an MDI for 42 days: mometasone furoate/formoterol (MF/F) 200 µg/10 µg, MF/F 400 µg/10 µg, fluticasone propionate/salmeterol (FP/S) 460 µg/42 µg, or placebo. Plasma cortisol concentrations were measured over 24 h on days -1 (baseline) and 42. Geometric mean ratio (GMR) and 90% CI for mean change from baseline to day 42 in 24-h plasma cortisol area under the curve (AUC) were calculated for each treatment. If the 90% CI for the GMRs fell within 70% to 143%, treatments were deemed comparable. RESULTS: Mean baseline cortisol AUCs were similar across groups. Mean cortisol effects (change from baseline) were similar for MF/F 400 µg/10 µg and FP/S 460 µg/42 µg (GMR, 119%; 90% CI, 101%-140%). Effects of MF/F 200 µg/10 µg on cortisol AUC were similar to placebo (GMR, 92%; 90% CI, 78%-110%), whereas MF/F 400 µg/10 µg and FP/S 460 µg/42 µg lowered cortisol AUC vs placebo (GMR, 78% [90% CI, 66%-92%] and 66% [90% CI 56%-78%], respectively). All treatments were generally well tolerated. CONCLUSIONS: MF/F 400 µg/10 µg or FP/S 460 µg/42 µg bid through an MDI led to similar reductions from baseline in mean cortisol AUC (22% and 34% lower than placebo, respectively), whereas the effect of MF/F 200 µg/10 µg was similar to placebo.

Pharmacokinetics and safety of single-dose ribavirin in patients with chronic renal impairment.

This open-label study assessed the pharmacokinetics of a single 400-mg oral dose of ribavirin in 6 healthy volunteers and 18 subjects with varying degrees of renal impairment (mild:creatinine clearance [CLcr] 61-90 mL/min/1.73 m², moderate: CLcr 31-60 mL/min/1.73 m(2), severe: CLcr 10-30 mL/min/1.73 m², n = 6 in each group). Blood and urine samples were collected pre-dose and up to 168 hours post-dose for pharmacokinetic analyses. Compared with control subjects, ribavirin area under the plasma concentration-time curve from time zero to the time of the final quantifiable sample (AUC(tf)) and maximum plasma concentration (C(max)) values were increased, and apparent clearance (CL/F), clearance (CLr), and amount excreted (Ae) values were reduced in subjects with renal impairment. Mean ribavirin AUC(tf) was increased 2- to 3-fold in patients with moderate-severe renal impairment compared with control subjects. Ribavirin CL/F and CLr were significantly correlated with CLcr. Single-dose ribavirin was safe and well tolerated in all subjects. The pharmacokinetics of ribavirin were substantially altered in subjects with stable chronic renal impairment, possibly reflecting changes in ribavirin metabolism associated with renal impairment.

Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease.

BACKGROUND: Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD. METHODS: This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14) with moderate-to-severe COPD: MF 400 µg/F 10 µg via a metered-dose inhaler (MF/F MDI; DULERA(®)/ZENHALE(®)) without a spacer device, MF/F MDI with a spacer, or MF 400 µg via a dry-powder inhaler (DPI; ASMANEX(®) TWISTHALER(®)) twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning) dose on day 5 of each period of the crossover. The geometric mean ratio (GMR) as a percent and the corresponding 90% confidence intervals (CI) were calculated for treatment comparisons. RESULTS: Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102) following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84) and (GMR 62%; 90% CI 52, 74), respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a similar adverse experience profile as that seen with MF DPI. All adverse experiences were either mild or moderate in severity; no serious adverse experience was reported. CONCLUSION: Systemic MF exposures were lower following administration by MF/F MDI compared with MF DPI. Additionally, systemic MF and formoterol exposures were lower following administration by MF/F MDI with a spacer versus without a spacer. The magnitude of these differences with respect to systemic exposure was not clinically relevant.

Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies.

PURPOSE: Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects of single oral doses of aprepitant when coadministered with dinaciclib. METHODS: As part of a phase 1 dose-escalation trial, subjects with advanced malignancies were randomized into a 2-period, multi-cycle, crossover study to investigate the effect of single doses of oral aprepitant on the pharmacokinetics of 29.6 mg/m(2) dinaciclib administered by 2-h intravenous infusion. During cycle 1 and cycle 2, subjects received dinaciclib with aprepitant in one cycle and dinaciclib without aprepitant in the other cycle; aprepitant was administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 and 3, along with standard dosing regimens of ondansetron and dexamethasone. RESULTS: Twelve patients completed the study; T (max) occurred approximately 2 h after the initiation of the infusion. The percent geometric mean ratio (dinaciclib + aprepitant vs. dinaciclib alone) was 106 % (90 % confidence interval [CI] 89-126 %) and 111 % (90 % CI 93-132 %) for dinaciclib C(max) and AUC([I]), respectively. The half-life and clearance of dinaciclib were similar, with or without aprepitant. CONCLUSIONS: Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib in patients with advanced malignancies.

Pharmacokinetics, safety, and tolerability of ribavirin in hemodialysis-dependent patients.

PURPOSE: This study describes the pharmacokinetics, safety, and tolerability of ribavirin in hemodialysis-dependent patients. METHODS: Six adult patients (4 male, 2 female) were recruited from a hemodialysis clinic where they were receiving regular hemodialysis sessions. Patients received a single oral 400-mg dose of ribavirin (2 × 200-mg capsules) after an overnight fast. A 4-h hemodialysis session was performed between 6 and 10 h post-dose. Plasma and urinary concentrations of ribavirin were determined using validated high-performance liquid chromatography/tandem mass spectrometric methods. RESULTS: Single oral doses of ribavirin 400 mg were safe and well tolerated in this population. Urinary excretion of ribavirin over 48 h was minimal (0.6 mg: approximately 0.14% of the dose). The mean amount removed during the 4-h hemodialysis session (9.6 mg) represented approximately 2.4% of the dose. CONCLUSIONS: Ribavirin hemodialysis clearance (CLhd = 74.5 ml/min) represented approximately 50% of the renal clearance (CLr) measured in subjects with normal renal function (CLr = 129 ml/min).

Evaluation of the exposure equivalence of oral versus intravenous temozolomide.

PURPOSE: Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration. METHODS: Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m(2) of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m(2) temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day. RESULTS: Ratio of log-transformed means (intravenous:oral) of area under the concentration-time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8-1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration. CONCLUSIONS: This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.

Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment.

Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.

Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men.

OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This randomized, open-label, parallel-group, multiple-dose study was conducted in healthy adult volunteers to assess the potential for a drug interaction between phenytoin and the posaconazole tablet formulation. METHODS: Subjects were randomly assigned for 10 days to one of the following treatments: posaconazole (200 mg once daily), phenytoin (200 mg once daily), or posaconazole (200 mg once daily) and phenytoin (200 mg once daily). Blood samples were collected on days 1 and 10 for pharmacokinetic evaluation of posaconazole and phenytoin concentrations. RESULTS: A total of 36 healthy men enrolled in the study. On day 1, the maximum plasma concentration (C(max)) and area under the concentration-time curve calculated from time 0-24 h post-dose (AUC(0-24)) were unchanged upon co-administration. At steady state (day 10), co-administration of posaconazole with phenytoin resulted in 44% (p = 0.012) and 52% (p = 0.007) decreases in posaconazole C(max) and AUC(0-24), respectively. These decreases in exposure corresponded with a 90% increase in steady-state clearance of orally administered posaconazole. Phenytoin C(max) and AUC(0-24) were not significantly altered upon co-administration of the two agents, 24% increase in C(max) (p = 0.196) and 25% increase in AUC(0-24) (p = 0.212) values, although inter-subject variability was observed within this group. CONCLUSION: Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin levels in some subjects, concomitant use of these agents should be avoided unless the benefit outweighs the risk.

Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus.

STUDY OBJECTIVE: To analyze the pharmacokinetic properties of the immunosuppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole. DESIGN: Two single-center, open-label pharmacokinetic studies of cyclosporine in a multiple-dose design and of tacrolimus in a one-sequence, crossover, single- and multiple-dose design. SETTING: One clinical investigative center in the United States and one in the United Kingdom. SUBJECTS: Four adult heart transplant recipients in the cyclosporine study and 36 healthy adult volunteers in the tacrolimus study. INTERVENTIONS: In the cyclosporine study, patients who took an established cyclosporine dose 3 times/day for 6 weeks or longer were given posaconazole 200 mg/day for 10 days. In the tacrolimus study, subjects received tacrolimus 0.05 mg/kg/day on days 1 and 14 and posaconazole 400 mg twice/day on days 7-14. MEASUREMENTS AND MAIN RESULTS: In the cyclosporine study, blood samples were collected on day 1 to determine cyclosporine pharmacokinetics and on day 10 to measure the pharmacokinetics of cyclosporine and posaconazole. Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14-29% for cyclosporine in three subjects. In the tacrolimus study, blood samples were collected on days 12-14 to assess posaconazole pharmacokinetics and on days 1 and 14 for as long 72 hours after dosing to evaluate tacrolimus pharmacokinetics. Posaconazole increased the maximum blood concentration and the area under the concentration-time curve for tacrolimus by 121% and 358%, respectively, on day 14 compared with day 1 (both p=0.001). In both studies, posaconazole pharmacokinetics were unaffected. CONCLUSION: These findings suggest that the dosage of cyclosporine or tacrolimus should be reduced when posaconazole therapy is started and that plasma levels of the immunosuppressant should be monitored during and at the discontinuation of posaconazole therapy so that dosages are adjusted accordingly. This recommendation is consistent with current standard of care for patients receiving cyclosporine or tacrolimus with concomitant azole antifungal therapy.

Pharmacokinetics of desloratadine in children between 2 and 11 years of age.

AIMS: The aim of the studies was to characterize the pharmacokinetics of desloratadine in healthy children and to determine the appropriate dose for paediatric patients 2-11 years old. METHODS: Two open-label, single-dose studies were carried out in healthy children between 2-5 (n = 18) and 6-11 years old (n = 18). On day 1, subjects received a single oral dose of desloratadine syrup (1.25 mg for 2-5 year olds or 2.5 mg for 6-11 year olds). Subjects were followed for an additional 4 days during which vital signs were measured daily and blood samples were collected periodically. RESULTS: Plasma desloratadine C(max) occurred at a median of 2.0 h after dosing in both age groups. Median values for the younger (2-5 years old) and older (6-11 years old) groups were 2.28 and 2.05 ng ml(-1), respectively. Arithmetic (and harmonic) mean t(1/2) (h) values for each group, respectively, were 16.4 (13.9) and 19.4 (15.8). Exposure to desloratadine was similar in both the younger and older age groups, with a median AUC(last) of 38.8 and 38.2 ng ml(-1) h, respectively. These data were similar to values in adults, who received 5 mg doses of desloratadine. No adverse events or clinically significant abnormal laboratory values were noted in either group. CONCLUSIONS: Single doses of desloratadine syrup (1.25 and 2.5 mg) were well tolerated in children 2-5 and 6-11 years old. Desloratadine exposure in children appears to be similar to that observed in adults, in whom efficacy has been established.

Desloratadine dose selection in children aged 6 months to 2 years: comparison of population pharmacokinetics between children and adults.

AIMS: The aim of this study was to identify the dose of desloratadine in children aged > or =6 months- < or =2 years that would yield a single-dose target exposure (AUC) comparable with that in adults taking 5 mg desloratadine as syrup. METHODS: In a phase 1, single-dose, open-label, pharmacokinetic study in 58 children aged > or =6 months- <1 year and > or =1 year- < or =2 years were randomly assigned to desloratadine syrup 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml), respectively. Because the volume of blood that could be collected from individual subjects was limited, a population pharmacokinetic approach was used to estimate the pharmacokinetics of desloratadine. Safety was assessed based on results of screening and postdose physical examinations, laboratory safety tests, vital signs, and adverse events. RESULTS: The apparent clearance (CL/F) of desloratadine, population estimate (%CV), in children aged > or =6 months- <1 year was 27.8 l h(-1) (35) and corresponding values in children > or =1 year- < or =2 years was 35.5 l h(-1) (51), compared with 137 l h(-1) (58) for adults. The CL/F ratios (children to adults) indicated that doses of 1 mg for > or =6 months- <1 year and 1.25 mg for > or =1 year- < or =2 years would result in similar systemic exposure to that observed in adults receiving the recommended 5 mg dose. Desloratadine was well tolerated with no safety issues. CONCLUSIONS: Doses of 1.0 and 1.25 mg in children aged > or =6 months- < or =2 years should result in an exposure to desloratadine similar to that of adults receiving doses of 5 mg.

Posaconazole plasma concentrations in juvenile patients with invasive fungal infection.

Posaconazole is an orally bioavailable triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. We evaluated plasma posaconazole concentration data from juvenile (younger than 18 years; n = 12) and adult (18 to 64 years; n = 194) patients who participated in a multicenter, phase 3, open-label study that assessed the efficacy and safety of posaconazole treatment for persons who were intolerant of or had invasive fungal infection refractory to standard antifungal therapies. With the exception of one juvenile patient who received 400 mg/day as a divided dose on the day of sample collection, all patients received posaconazole at 800 mg/day as an oral suspension in divided doses. Plasma samples were analyzed through a validated liquid chromatographic-tandem mass spectrometric method with a lower limit of quantitation of 1 ng/ml. Because plasma posaconazole concentrations are relatively constant at steady state, the average of all plasma concentrations (C(av)) for each patient was calculated to provide a single steady-state plasma posaconazole concentration. A blinded data review committee reviewed all treatment outcomes. Variable posaconazole plasma concentrations were observed within both the juvenile and adult populations. Mean (median [range]) C(av) values for juvenile and adult patients were 776 ng/ml (579 ng/ml [85.3 to 2,891 ng/ml]) and 817 ng/ml (626 ng/ml [0 to 3,710 ng/ml]), respectively. Overall success rates and adverse event profiles were comparable. In conclusion, posaconazole concentrations in plasma were similar for juvenile and adult patients, suggesting that clinical outcomes are expected to be similar in adults and children with refractory invasive fungal infection.