Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: pharmacology, toxicity, and response.

Preclinical studies have suggested that synergistic antitumor toxicity occurs when methotrexate (MTX) is administered prior to 5-fluorouracil (FUra). A protocol of sequenced, overlapping infusions of MTX and FUra was designed to achieve 5 microM MTX serum levels lasting 36 h and 1 to 5 microM FUra levels lasting 24 h, with leucovorin started at the end of the MTX infusion. Thirty-nine patients with metastatic neoplasms received a total of 127 treatment courses; two-thirds of the patients had received prior treatment with radiation therapy or chemotherapy; most of the latter treatment regimens included MTX or FUra. In three patients, the duration of FUra infusion was prolonged up to 72 h to determine the toxic limits of therapy. Blood samples were collected during treatment courses to estimate the half-lives and total-body clearances of MTX and FUra. The initial serum half-lives and total-body clearances of both MTX and FUra appeared within the range of reported normal values. The terminal half-life of MTX appeared less than previously reported values, and there appeared to be a substantial delay in achieving a FUra steady-state concentration; these two differences may have resulted from either the prolonged intervals of drug infusion or from metabolic interaction between the two drugs. During the 127 courses of treatment, nearly one-half of the patients experienced mild toxicity occurring after at least one treatment, but this toxicity was predominantly Grade I mucositis and/or diarrhea. Of the three patients who received extended intervals of FUra infusion, none was able to tolerate more than 48 h of FUra without developing mucositis. Thirty-four patients were evaluable for response; no one experienced a complete response, but 11 (32%) patients had either a partial or minimal response. Adenocarcinomas as a group, arising from the lung, gut, breast, and unknown site, appeared to respond best. Sequenced MTX-FUra infusion by this schedule is a generally well-tolerated regimen that deserves further clinical assessment.

Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria.

This prospective trial investigated the population pharmacokinetics of piperaquine given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard 3-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three-compartment model with first-order absorption described the data well. Age had a statistically significant effect (P < 0.005) on clearance/bioavailability in a model that accounts for allometric scaling. Simulations demonstrated that higher doses in all children, but especially in those with lower weight for age, are required for adequate piperaquine exposure, although safety and tolerance will need to be established. These findings support other evidence that both weight- and age-specific guidelines for piperaquine dosing in children are urgently needed.

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 interindividual 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 intraindividual 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.

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

OBJECTIVES: To characterize the population dose-response and concentration-response relationships of felodipine and to investigate the influence of patient variables on these relationships. METHODS: We studied 239 evaluable patients with mild to moderate essential hypertension in a multicenter, randomized, double-blind dose-escalation trial, followed by an optional open-label maintenance phase for the remainder of 1 year. Extended-release felodipine (2.5 to 20 mg) monotherapy was given once daily. Felodipine plasma concentration and sitting diastolic blood pressure were measured at approximately 2 and 24 hours after drug administration. Analysis, performed with use of the population approach (NONMEM program), accounted for baseline and placebo effects. RESULTS: A saturation (Emax) model best described both felodipine dose response (only 24-hour postdose data) and concentration response. The maximum effect (Emax) characterizing dose response was found to increase linearly with age and was estimated to be 20.6 mm Hg in the typical individual (60 years of age). The dose at which 50% of the maximum effect is achieved (D50) was estimated to be 11.1 mg. The Emax characterizing concentration response also increased linearly with age and was estimated to be 27.8 mm Hg for the typical individual. The concentration at which 50% of the maximum effect is achieved (C50) was related to plasma renin activity (PRA) by the following: (21.6.PRA)/(0.25 + PRA) nmol/L; its value in the typical individual was estimated to be about 16.9 nmol/L. Felodipine (oral) clearance decreased with increasing age, up to 60 years, and was larger in black patients. CONCLUSIONS: The effects of age on felodipine pharmacokinetics and pharmacodynamics lead to a heightened antihypertensive response in the elderly. A starting dose of 2.5 mg daily is recommended, especially in elderly patients.

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.

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.

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.

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 metformin's 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 (CL*cr; 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] = alpha + beta.CL*cr + gamma.CL*cr.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.

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.

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.

Pharmacodynamic analysis of analgesic clinical trials using empirical methods.

Data from analgesic clinical trials have characteristics such as ordered categorical longitudinal responses with repeated measures, delay of effect with respect to analgesic plasma concentration, and right-hand censoring of response due to remedication. In order to determine the concentration-effect relationship of such data, we propose convolving an empirical function for plasma concentration, in the form of broken lines which connect each pair of neighboring observations, with a monoexponential function, to generate "effect site concentration." Effect site concentration and time are used, simultaneously, as independent variables in the fit of the model for the logit of the probability of having a specific pain relief (PR) score at each time point pre-remedication, via maximum likelihood. Using corresponding effect site concentration, the probabilities of having specific PR scores post-remedication are predicted via the concentration-response relationship established. The overall (pre- and post-remedication) predictions and corresponding standard errors for the responses are then estimated. Inference of the PR scoring, using a posterior method, is proposed. An illustration using real data is used to demonstrate these methods.

Pharmacodynamic analysis of analgesic clinical trials: nonlinear mixed-effects logistic models.

In the development of an analgesic product, placebo-controlled clinical trials in patients with defined pain are used to study the dose-time-response relationship of the drug. In such trials, the response is usually an ordered categorical variable with longitudinal and subject-specific repeated measurements. The primary causal variables are time and analgesic concentration. The response may be informative right-hand censored because remedication with a known analgesic may be given if a patient has inadequate pain relief. Mixed-effects logistic models are used to estimate the probabilities of having certain pain relief or pain severity scores. A jackknife method is proposed to estimate the standard errors of parameter estimates. Posterior estimates of these probabilities, or of the scores themselves, allow the evaluation of efficacy for an analgesic. In this evaluation, therapeutic as well as statistical significance is assessed. Two case studies, one focusing on pain relief and the other on pain severity, are used to demonstrate the approach. The level of baseline pain appears to be a determinant of the pattern of response.

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.

Variational analysis of the transdermal delivery rate from two prototypical ethanol-water nitroglycerin TTS devices and Transderm-Nitro 10 in the normal population.

The performance of two prototypical ethanol-water flux-enhanced transdermal therapeutic systems were compared to the performance of commercial Transderm-Nitro 10. This was a single-center, open-label, three-treatment, randomized crossover study in six healthy subjects who completed the study. Concurrent with each transdermal treatment, an infusion of the stable isotope [15N]3-nitroglycerin was administered. The use of double isotope methodology was incorporated into this study to minimize the variation introduced by fixed-effect error on the evaluation of transdermal flux. The objectives of this study were to isolate experimentally and characterize the average flux enhancement of each prototype, to determine the temporal profile of delivery, and to evaluate the components of variance of drug delivery from each transdermal system. The results of this study showed that the two flux-enhanced transdermal systems with different fill volumes both produced flux enhancement factors of 2 to 3 relative to Transderm-Nitro 10. Prototype B demonstrated a 57% reduction in intersubject variation relative to Transderm-Nitro 10 indicative of enhanced control of drug permeation across a subject population. Prototype A, while reducing intersubject variations, was less than optimal. Both prototypes demonstrated comparable intrasubject variation relative to Transderm-Nitro 10, indicating similar stability for within-subject transdermal drug delivery. The flux enhancement and variational properties of Prototype B were consistent with those intended based on mechanistic considerations of mutual nitroglycerin and ethanol-coupled transdermal delivery.

In vitro-in vivo relationship of oral extended-release dosage forms.

PURPOSE: A method to establish the in vitro-in vivo relationship of oral extended-release products is proposed. METHODS: The approach utilizes incremental amounts of drug released and absorbed within defined time intervals, to construct a chi2 distributed variable for testing in vitro-in vivo similarity. RESULTS: A case study is used to demonstrate that the similarities between incremental values of in vivo absorbed and in vivo dissolved fractions are distinguishable for different dissolution profiles despite naturally significant linear correlations between cumulative in vivo absorbed and in vitro dissolved fractions (with different dissolution tests) of an oral extended-release product. CONCLUSIONS: The method enables investigators to compare different in vitro dissolution profiles of an oral extended-release product to find an optimized dissolution profile to be the surrogate of the in vivo release process of the product.

Pharmacokinetics of oral extended-release dosage forms. I. Release kinetics, concentration, and absorbed fraction.

In this study, we derive pharmacokinetic models for oral extended-release (OER) drug products with defined in vivo release kinetics (IVRK) and a compartmental system. Fitting the model to clinical data, we were able to examine the correlation between released and absorbed fractions. Furthermore, we found that absorbed fractions of OER products can be expressed by absorption rate and release duration only. The expression is unchanged in different compartmental systems with the same IVRK, implying that the IVRK drives the pharmacokinetic system of an OER product. The apparent absorption rate constant of an OER product can be estimated by solving an implicit equation using observed concentrations. We also propose a new method for calculating absorbed fractions, which is more accurate than Loo-Riegelman method. Ultimately, these methods may permit optimally designed OER products.

A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow.

The H2-receptor antagonist cimetidine has been reported to decrease the hepatic clearance of numerous drugs by inhibiting cytochrome P-450 metabolism, decreasing liver blood flow or both. In this open-label, randomized crossover study we determined whether therapeutic doses of famotidine, a newer H2-receptor antagonist, has similar effects. Ten healthy subjects received single doses of both phenytoin 100 mg orally and indocyanine green intravenously without other treatment, and then again during treatment with famotidine or cimetidine. After a drug-free period, this sequence was repeated with the alternate H2-receptor antagonist. Cimetidine decreased the plasma clearance of phenytoin by 16% +/- 14% (mean +/- s.d.), but was not found to have a significant influence on phenytoin volume of distribution or terminal elimination rate constant nor on blood clearance of indocyanine green. Famotidine was not found to alter either phenytoin or indocyanine green kinetics.

Food intake and dosage level, but not tablet vs solution dosage form, affect the absorption of metformin HCl in man.

The pharmacokinetics of four single-dose treatments of the metformin administered orally (as the HCl salt) were compared in 24 healthy subjects: 500 mg and 850 mg tablets and 850 mg solution fasting and 850 mg tablet with food. Solution and tablet formulations are bioequivalent. Bioavailability of a 500 mg tablet is 14% greater than that of an 850 mg tablet. Compared with the fasting state, bioavailability is 24% lower, and the peak concentration delayed about 37 min when an 850 mg tablet is administered with food.