Nancy C. Sambol

Kidney Function and Age Are Both Predictors of Pharmacokinetics of Metformin

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle‐age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850‐mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high‐performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35–40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformins appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74–78% lower than in the healthy young/middle‐age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23–33% lower than in the young/middle‐age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CLcr*; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = α + β·CLcr* + γ · CLcr*·age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non‐insulin‐dependent diabetes) population.

Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Subjects and Patients with Noninsulin‐Dependent Diabetes Mellitus

This study was conducted to assess the effect of noninsulin‐dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose‐dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single‐blind single‐dose treatments of metformin HCl (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple‐dose treatment of 850 mg metformin HCl (3 times daily for 19 doses). After each single‐dose treatment and the final dose of the multiple‐dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple‐dose treatment versus single‐dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700‐mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.

Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity

BACKGROUND Morbidly obese patients undergoing gastric bypass surgery are at risk for postoperative venous thromboembolism. Evidence-based recommendations regarding the dosing and duration of thromboprophylaxis are lacking for morbidly obese surgical patients. The aims of this study were to evaluate the safety and efficacy of an extended duration, body mass index (BMI)-stratified enoxaparin thromboprophylaxis regimen in patients undergoing Roux-en-Y gastric bypass and to determine the resultant antifactor Xa (AFXa) activity in morbidly obese surgical patients. METHODS In this prospective open trial, 223 patients (75% female, mean BMI 50.4 kg/m2) undergoing Roux-en-Y gastric bypass were assigned to receive enoxaparin 40 mg (BMI <or=50 kg/m2), n = 124) or 60 mg (BMI >50 kg/m2), n = 99) every 12 hours during hospitalization and once daily for 10 days after discharge. The AFXa levels were monitored serially, and dose adjustments were made for results outside the target prophylactic range (.2-.4 IU/mL +/- 10%) after the third dose. The safety and efficacy outcomes were major bleeding and venous thromboembolism. RESULTS Roux-en-Y gastric bypass was performed laparoscopically in 208 subjects (93%). The duration of surgery averaged 99.5 +/- 31 minutes, and the median length of hospitalization was 3 days. Target prophylactic AFXa concentration was achieved by 74% of patients after the third enoxaparin dose; none reached the full anticoagulation concentration. One patient developed nonfatal venous thromboembolism (.45%). Four patients required transfusion (1.79%). Bleeding was not associated with a high AFXa concentration. CONCLUSION This BMI-stratified, extended enoxaparin dosing regimen provided well-tolerated, effective prophylaxis against venous thromboembolism in patients undergoing gastric bypass surgery.

Study designs for dose‐ranging

Premarketing dose‐ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run‐in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose‐ranging studies be changed. We believe one must begin with a parametric model for patient‐specific dose‐response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel‐dose design can provide only poor information about the distribution of dose‐response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient‐specific dose‐response model is used, a dose‐escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.

Interaction Between Structural, Statistical, and Covariate Models in Population Pharmacokinetic Analysis

The influence of the choice of pharmacokinetic model on subsequent determination of covariate relationships in population pharmacokinetic analysis was studied using both simulated and real data sets. Simulations and data analysis were both performed with the program NONMEM. Data were simulated using a two-compartment model, but at late sample times, so that preferential selection of the two-compartment model should have been impossible. A simple categorical covariate acting on clearance was included. Initially, on the basis of a difference in the objective function values, the two-compartment model was selected over the one-compartment model. Only when the complexity of the one-compartment model was increased in terms of the covariate and statistical models was the difference in objective function values of the two structural models negligible. For two real data sets, with which the two-compartment model was not selected preferentially, more complex covariate relationships were supported with the one-compartment model than with the two-compartment model. Thus, the choice of structural model can be affected as much by the covariate model as can the choice of covariate model be affected by the structural model; the two choices are interestingly intertwined. A suggestion on how to proceed when building population pharmacokinetic models is given.

Pharmacokinetics, pharmacodynamics, and minimum effective clinical dose of intravenous nicardipine

Nicardipine hydrochloride was administered intravenously to two groups of hypertensive patients: one group of 37 patients with mild to moderate hypertension and one group of 20 patients with severe hypertension. In the first group, doses of 0.5, 1, 2, and 4 mg/hr, as well as placebo, were infused for 48 hours in a double‐blind fashion. Blood pressure and heart rate were monitored for this period and for the 24 hours after the infusion was discontinued. Significant decrements in blood pressure were noted with all doses; 4 mg/hr produced lowering that was greater than all other doses; 1 and 2 mg/hr produced lowering that was greater than 0.5 mg/hr but that were not different from each other. Excellent correlation of blood pressure reduction and plasma level was observed and linear kinetics existed. In the severe hypertensive patients, 1, 2, 4, 5, and 8 mg/hr were infused to established minimal and ineffective doses. One milligram per hour was an ineffective dose; 4, 5, and 8 mg/hr all produced significant reductions over the course of the study that were undistinguishable from each other. Two milligrams per hour produced modest reductions in blood pressure. Blood pressure reduction also correlated with plasma levels in the severe hypertensive group.

Plasma Pharmacokinetics and Tissue Biodistribution of Boron Following Administration of a Boronated Porphyrin in Dogs

This study was undertaken to determine the plasma pharmacokinetics and tissue biodistribution of boron in dogs following the administration of a boronated porphyrin (BOPP) compound, a potential sensitizing agent for binary therapies of cancer. An intravenous dose of 35 mg/kg of BOPP was administered to a total of sixteen dogs and plasma samples obtained at multiple time points for up to 28 days after administration. Groups of four dogs each were studied for 25, 79, 240, and 672 h. At the end of each study period, subjects were sacrificed and tissue samples obtained. Boron concentrations were determined for all tissue and plasma samples, and pharmacokinetic parameters were determined using mixed effects modeling. Plasma boron levels displayed triexponential kinetics with a long terminal half-life and small volume of distribution. Liver, lymph node, adrenal, and kidney tissues accumulated the highest levels of boron, with very low levels associated with most tissues of the head. We conclude that BOPP has pharmacokinetic and tissue distribution properties that suggest that it may be a suitable compound for use as a sensitizing agent in binary therapy of cancer.

Felodipine population dose-response and concentration-response relationships in patients with essential hypertension

To characterize the population dose‐response and concentration‐response relationships of felodipine and to investigate the influence of patient variables on these relationships.

Population dose versus response of betaxolol and atenolol: A comparison of potency and variability

The dose‐response curves of betaxolol and atenolol were compared in 140 patients with mild to moderate essential hypertension. Patients with a supine diastolic blood pressure of 95 to 115 mm Hg at the end of a 4‐week single‐blind placebo washout phase were randomized (double‐blind) to receive either betaxolol or atenolol in a dose‐escalation manner. The dose (5 mg, 10 mg, and 20 mg betaxolol; 25 mg, 50 mg, and 100 mg atenolol) was increased if the supine diastolic blood pressure remained greater than 90 mm Hg after 4 weeks at each level. The final dose in the escalation phase was continued for an additional 12 weeks and then followed by a 2‐week placebo phase. The data were analyzed with a population model using the program NONMEM (nonlinear mixed effects model). Atenolol exhibited a graded dose‐response curve, whereas the lowest dose of betaxolol produced maximum or near‐maximum effect. The estimated maximum effect (drug plus possibly unmeasured placebo effect) was similar for both treatments, about 13 mm Hg (95% confidence interval, 10 to 15 mm Hg). A trend toward less inter‐individual variability (coefficient of variation) was apparent for betaxolol compared to atenolol, 19% (95% confidence interval, 0% to 29%) versus 31% (95% confidence interval, 0% to 47%). The intra‐individual variability (standard deviation) in supine diastolic blood pressure, 5.9 mm Hg (95% confidence interval, 5.2 to 6.5 mm Hg), did not differ significantly between drugs despite significantly greater intraindividual variability (coefficient of variation) in atenolol concentrations, 62% (95% confidence interval, 48% to 73%) versus 26% (95% confidence interval, 22% to 29%) for betaxolol.

CYP2A6 genotype but not age determines cotinine half-life in infants and children.

The formation of cotinine, the main proximate metabolite and a biomarker of nicotine exposure, is mediated primarily by cytochrome P450 (CYP)2A6. Our aim was to determine whether higher cotinine levels in young children exposed to secondhand smoke (SHS) are a result of age‐related differences in pharmacokinetics. Forty‐nine participants, aged 2–84 months, received oral deuterium‐labeled cotinine, with daily urine samples for up to 10 days for cotinine half‐life measurement. DNA from saliva was used for CYP2A6 genotyping. The estimate of half‐life using a mixed‐effect model was 17.9 h (95% confidence interval: 16.5, 19.3), similar to that reported in adults. There was no statistically significant effect of sex, race, age, or weight. Children with normal‐activity CYP2A6*1/*1 genotypes had a shorter half‐life than those with one or two reduced‐activity variant alleles. Our data suggest that higher cotinine levels in SHS‐exposed young children as compared with adults are due to greater SHS exposure rather than to different cotinine pharmacokinetics.