Armen P. Melikian

The Pharmacokinetics and Pharmacodynamics of Fludarabine Phosphate in Patients with Renal Impairment: A Prospective Dose Adjustment Study

A significant number of chronic lymphocytic leukemia, follicular non-Hodgkins lymphoma and Waldenströms macroglobulinemia patients, treated with fludarabine phosphate (fludarabine), are elderly with diminished renal function. Since the kidney eliminates approximately 60% of fludarabines primary metabolite (F-ara-A), dose modification is necessary for all patients with impaired renal function including elderly patients. In this study, 22 patients with varying levels of renal function received a single intravenous dose of fludarabine (25 mg/m3), followed one week later by five (one per day) doses that were adjusted according to three predefined creatinine clearance (CLcr) levels. Relationships between renal function and F-ara-A clearance, F-ara-A exposure and F-ara-A -related toxicities were examined. The results demonstrate that total F-ara-A clearance correlated with CLcr and that F-ara-A exposure levels and patient toxicity profiles were similar across treatment groups. In conclusion, the CLcr-based fludarabine dose adjustments used in this study provided reasonably equivalent F-ara-A exposure with acceptable safety in patients with varying degrees of renal function.

Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis

Metoclopramide kinetics were examined in 24 adult patients with diminished renal function and in eight healthy subjects with normal renal function. Creatinine clearance correlated with metoclopramide plasma clearance, renal clearance, nonrenal clearance, and elimination t½. Regardless of renal function, renal clearance accounted for ≤21% of total plasma clearance. Nonrenal clearance was reduced in patients and accounted for most of the reduction in plasma clearance. The comparatively small plasma clearances in patients imply that maintenance doses should be reduced accordingly to avoid drug cumulation. Metoclopramide clearance by hemodialysis was also assessed in four patients. Metoclopramide losses from hemodialysis were relatively small compared to estimates of total body metoclopramide stores. Compensatory dosage increases are probably unnecessary for most patients. These data also suggest that hemodialysis is not likely to be effective in metoclopramide overdose.

Population pharmacokinetics and pharmacodynamics of sotalol in pediatric patients with supraventricular or ventricular tachyarrhythmia.

Aims: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT).Methods: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m2 sotalol, extensive blood samples (n=10) were taken. The PK–PD study used a dose escalation design with doses of 10, 30, and 70 mg/m2, each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECGs were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology.Results: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CVs) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CVs in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CVs for SL and E0 were 86.7 and 14.4%, respectively.Conclusions: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc–C relation, while the RR–C relation shows age or BSA dependency.

Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with supraventricular and ventricular tachyarrhythmia

This pharmacokinetic‐pharmacodynamic study was designed to define the steady‐state relationship between pharmacologic response and dose or concentration of sotalol in children with cardiac arrhythmias, with an emphasis on neonates and infants.

Single-dose pharmacokinetics of sotalol in a pediatric population with supraventricular and/or ventricular tachyarrhythmia.

The pharmacokinetics (PK) of the antiarrhythmic sotalol, which elicits Class III and beta‐blocking activity, has not been adequately defined in a pediatric population with tachyarrhythmias. The goal of this single‐dose study with administration of sotalol HCl at a dose level of 30 mg/m2 body surface area (BSA) was to define the PK of the drug in the following four age groups: neonates (0–30 days), infants (1 month to 2 years), younger children (> 2 to < 7 years), and older children (7–12 years) with tachyarrhythmias of either supraventricular or ventricular origin. The drug was administered in an extemporaneously compounded syrup formulation prepared from the tablets containing sotalol HCl. For safety, vital signs and adverse events were recorded and the QTc interval and heart rate telemetrically monitored. Scheduled blood samples were taken over a 36‐hour time interval following dose administration. The drug concentrations in plasma were measured by a sensitive and specific LC/MS/MS assay. Standard compartment model‐independent methods were applied to compute the salient PK parameters of sotalol. Twenty‐four clinical sites enrolled 34 patients. Thirty‐three had analyzable data. Sotalol was rapidly absorbed, with mean peak concentrations occurring 2 to 3 hours after administration. The elimination of sotalol was characterized by an average half‐life of between 7.4 and 9.2 hours in the four age groups. There existed statistically significant linear relationships between apparent total clearance (CL/f) or apparent volume of distribution (VΛz/f) after oral administration and the covariates BSA, creatinine clearance (CLcr), body weight (BW), or age. The best predictors for CL/f were CLcr and BSA, whereas BW best predicted the VΛz/f. The total area under the drug concentration‐time curve in the smallest children with a BSA < 0.33 m2 was significantly greater than that in the larger children. This finding indicated that the BSA‐based dose adjustment used in this study led to a larger exposure in the smallest children, whereas the exposure to the drug was similar in the larger children. The dose of 30 mg/m2 was tolerated well. No serious drug‐related adverse events were reported. It can be concluded that the PK of sotalol in the pediatric patients depended only on body size, except for the neonates and smallest infants in whom the disposition of sotalol was determined by both body size and maturation of eliminatory processes.

Bioavailability of Potassium From Three Dosage Forms: Suspension, Capsule, and Solution

A crossover study was performed in 28, healthy, male volunteers to determine the bioavailability of potassium from a suspension containing microencapsulated potassium chloride compared with that from a marketed microencapsulated potassium chloride capsule and a marketed potassium chloride solution. The 20‐day study consisted of four, five‐day periods. In three of the periods, a single, 40‐mEq dose of one of the potassium formulations was administered; no drug treatment was given in the remaining period so that the amount of potassium contributed by dietary sources could be determined. Meals were served that provided controlled amounts of potassium and sodium.

Bioavailability and Disposition of Metoclopramide after Single‐ and Multiple‐Dose Administration in Diabetic Patients with Gastroparesis

The disposition of metoclopramide after acute and chronic administration was determined in four diabetic patients with gastroparesis who had a creatinine clearance of 70.8 ±10.7 mL/min (mean ± SD). Single, 10‐mg oral and intravenous doses were administered on days 1 and 2, respectively, followed by 10 mg orally every six hours for three weeks. A second, 10‐mg intravenous bolus dose was administered on the last morning of chronic therapy. Metoclopramide concentrations were determined by high performance liquid chromatography. The elimination half‐life, steady‐state volume of distribution, and total body clearance after the initial intravenous dose were 3.9 ± 1.2 hr, 2.7 ± 0.3 L/kg, and 0.57 ± 0.14 L/hr/kg, respectively. The initial bioavailability was 67.7 ± 12.6%. After three weeks of chronic therapy, no significant differences in total body clearance (0.72 ± 0.42 L/hr/kg) or bioavailability (77.5 ± 16.8%) were observed. Thus the pharmacokinetics and bioavailability of metoclopramide were not altered during chronic therapy in these diabetic patients.

Simultaneous Estradiol and Levonorgestrel Transdermal Delivery from a 7-day Patch: In Vitro and In Vivo Drug Deliveries of Three Formulations

ABSTRACT A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara ProTM.

Quinidine assays: enzyme immunoassay versus high performance liquid chromatography

Plasma quinidine results determined by enzyme multiplied immunoassay (EMIT) (Syva) were compared with results from a quinidine-specific high performance liquid chromatographic (HPLC) assay. During a clinical study, 16 patients with stable ventricular arrhythmias were treated with three oral quinidine preparations given during three consecutive 3-day periods. Seventeen plasma samples were drawn from each patient at steady-state during each period. Each specimen was divided into two portions, one for assay by EMIT and the other for assay by HPLC. EMIT assays were done on a Syva Autolab 6000 System using Syva quinidine kits and bilevel Ortho Diagnostics controls. The overall mean (+/- SD) quinidine concentrations by EMIT and HPLC were 2.16 +/- 0.58 and 1.81 +/- 0.60, respectively, n = 816, with a mean overall EMIT/HPLC ratio of 1.23 +/- 0.18. Mean ratios in individual patients ranged from 1.01 to 1.56; the average of mean individual ratios was 1.23 +/- 0.13. The EMIT assay, which also reports dihydroquinidine and small amounts of quinidine metabolites as quinidine, reported quinidine values that averaged 1.2-fold greater than results from a quinidine-specific HPLC method.

Pharmacokinetics of continuous once‐a‐week combination 17β‐Estradiol/Low‐ or high‐dose levonorgestrel transdermal delivery systems in postmenopausal women

Two open‐label, randomized, two‐period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone‐binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy.