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L J Lesko

Publications and source records attributed to L J Lesko.

At least 37 records · Page 2Linked to original sources
PubMed1999

In vitro metabolic interaction studies: experience of the Food and Drug Administration.

A total of 194 new molecular entities approved by the Food and Drug Administration between 1992 and 1997 were surveyed to determine the role of in vitro metabolic interactions in the conduct of drug-drug interaction studies and to examine the methods used in these studies. Approximately 30% of the submissions were found to have in vitro metabolism-based interaction studies, most of which were inhibitory in nature. Chemical inhibition was the most commonly used approach in studying drug interactions in vitro. In this article, an attempt to assess the quality of the chemical inhibition approach was made. Four areas were found to be often overlooked: (1) incubation time and concentrations of the drug, (2) the difference between inhibition constant (k(i)) and 50% inhibitory concentration (IC50) values, (3) the substrate-dependent inhibition potential, and (4) the metabolic genotype or phenotype of the liver donor. We discuss the pitfalls in estimating drug interactions when these four areas are overlooked.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed1999

Development of in vivo bioequivalence methodology for dermatologic corticosteroids based on pharmacodynamic modeling.

BACKGROUND: Dermatologic corticosteroid products produce skin blanching that is related to clinical potency and dose. (For application of the vasoconstrictor assay to bioavailability and bioequivalence assessment, dose is defined in terms of duration of treatment exposure [dose duration], so the terms dose and dose duration have been used interchangeably). The vasoconstrictor assay is the method of choice to assess dermatologic corticosteroid products bioequivalence if dose-response is validated. This article examines dose-response validation to meet objectives of US Food and Drug Administration (FDA) bioequivalence guidance for dermatologic corticosteroid products. METHODS: An exploratory dose-response study was conducted to determine applicability of the empirical maximum effect (Emax) model to the individual subject and population dose-response relationships of six dermatologic corticosteroid product creams that varied from the most to the least potent classes. Products were applied to the skin of 10 healthy subjects in each of two dosing periods for dose durations of 0.5, 1, 2, and 6 hours. Skin blanching was measured by reflectance colorimeter through 24 hours after application. Area under the effect curve (AUEC) was determined for each dose duration. An Emax model was fitted to the AUEC versus dose duration data. A similar analysis was conducted for a bioequivalence study on two formulations of a dermatologic corticosteroid product in 40 healthy subjects. RESULTS: In the exploratory study, the number of individual subject data sets for which the Emax model provided an acceptable fit generally increased with the potency of the dermatologic corticosteroid product. On the basis of population modeling, dose-response data of all products, except the lowest potency cream, were adequately described by the Emax model. Values for population ED50 (the dose duration required to achieve 50% of the fitted AUECmax value) decreased with increase in dermatologic corticosteroid product potency. CONCLUSIONS: Acceptable model fits to all individual subject dose-response data were not achieved for any dermatologic corticosteroid product. However, population dose-responses were adequately described by the Emax model. On the basis of these data, the optimal dose duration used for comparison of multisource dermatologic corticosteroid products is recommended to be equal to the ED50 based on population modeling of pilot dose-response study data.

Adrenal Cortex Hormones↗
PubMed1999

FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling.

Recent advances in in vitro metabolism methods have led to an improved ability to predict clinically relevant metabolic drug-drug interactions. To address the relationships of in vitro metabolism data and in vivo metabolism outcomes, the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research, Food and Drug Administration, evaluated a number of recently approved new drug applications. The goal of these evaluations was to determine the contribution of in vitro metabolism data in (1) predicting in vivo drug-drug interactions, (2) determining the need to conduct an in vivo drug-drug interaction study, and (3) incorporating findings into drug product labeling. Ten cases are presented in this article. They fall into two major groups: (1) in vitro data were predictive of in vivo results, and (2) in vitro data were not predictive of in vivo results. Discussion of these cases highlights factors limiting predictability of in vivo metabolic interactions from in vitro metabolism data. The integration of these findings into drug product labeling is also discussed.

Data Collection↗
PubMed1999

Assessment of the quality and quantity of drug-drug interaction studies in recent NDA submissions: study design and data analysis issues.

This report investigates the quality and quantity of drug-drug interaction studies in recent new drug applications (NDAs). Eighty-nine studies contained in 14 NDAs submitted between December 1995 and November 1996 to the U.S. Food and Drug Administration (FDA) were reviewed. The results indicated that the median number of clinical drug-drug interaction studies per NDA was 6, almost double that of a 1994-1995 survey. In vitro metabolism data were present in 70% of the submissions. More than 50% of the submissions contained interaction studies using a battery of drugs (cimetidine, digoxin, or warfarin) without optimal use of the in vitro metabolism or in vivo mass balance data. Various study designs using a median number of 12 subjects were employed in the evaluation of drug-drug interactions. Some of the important study design factors such as dose size, dosing regimen, dosing duration, and timing of coadministration were considered, although not consistently, by the sponsors in their study design. Seventy-five percent of the studies used normal, healthy male subjects, and 25% used patients for whom the new molecular entities were intended. In 33% of the studies, female subjects were also recruited. Although the majority (80%) of the submissions still used p-values to determine the significance of drug interactions, 30% used a more relevant equivalence approach with 90% confidence intervals for key pharmacokinetic and/or pharmacodynamic parameter ratios to assess the extent of drug interactions. Overall, 82% of the studies concluded no interaction. Although population pharmacokinetic analysis can be a useful tool in studying drug-drug interactions, only 21% of the submissions used this approach. In summary, this assessment reveals that the quantity and quality of drug-drug interaction studies in NDAs have improved over the years. These improvements, as well as others that can be implemented, should result in more informative labeling and better patient care. FDA guidance for industry dealing with the design, analysis, and labeling language of in vivo metabolic drug-drug interactions has been developed to assist sponsors and FDA reviewers with these issues.

Clinical Trials as Topic↗
PubMed1998

The relative bioavailability and in vivo-in vitro correlations for four marketed carbamazepine tablets.

PURPOSE: To determine if three marketed generic carbamazepine tablets were bioequivalent to the innovator formulation, as well as to each other. In addition, to examine in vivo-in vitro relationships among the four formulations. METHODS: Each formulation was given as a single dose to 18 healthy male and female subjects using a crossover design. Blood samples were collected for 169 hr. Carbamazepine was assayed by HPLC with UV detection. RESULTS: In vivo fraction absorbed plots indicated that the three generic formulations were absorbed more rapidly than the innovator product, and the mean time of maximum plasma concentration was 6-7 hr sooner for the generic formulations. The mean maximum plasma concentration ranged from 17-19 percent higher for the generic products compared to the innovator, and the 90% confidence limits for Cmax data ranged from 11 1% to 126%. The mean AUC(0-infinity) for the generic products ranged from 101-104% compared to the innovator, and the confidence limits for AUC ranged from 97-108%. CONCLUSIONS: The generic products were all more rapidly absorbed than the innovator, but simulations of steady-state concentrations indicated that it would be unlikely that these differences would have any significant clinical effect. An excellent association was seen between the Cmax and the percent of drug dissolved in vitro. The correlation was used to accurately predict the Cmax of four other 200 mg tablets evaluated in an earlier study.

Adult↗
PubMed1998

Lack of in vivo/in vitro correlations for 50 mg and 250 mg primidone tablets.

PURPOSE: To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. METHODS: Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. RESULTS: Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0-infinity) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0-infinity) among the four 250 mg tablets were less than 7%. CONCLUSIONS: Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.

Adult↗
PubMed1998

The impact of formulation and process changes on in vitro dissolution and the bioequivalence of piroxicam capsules.

The purpose of this research was to determine the effect of major compositional changes on the bioavailability of piroxicam from immediate-release formulations filled in hard gelatin capsules. The capsules were manufactured according to a 2(5-1) + star point (resolution V) experimental design to investigate the effects of sodium lauryl sulfate level, magnesium stearate level, lactose/microcrystalline cellulose ratio, piroxicam particle size, and lubricant blending time. Sodium lauryl sulfate level, lactose level, and piroxicam particle size were the most important main effects affecting dissolution. Lubricant level and lubricant blending time were either not significant (5% level) or were among the lowest ranking of factors affecting dissolution in standardized pareto analysis. Three of these formulations exhibiting slow, medium, and fast dissolution were compared to a single lot of the Innovator (commercial) product in a small bioavailability study. The slow formulation did not meet the USP dissolution specification for piroxicam capsules. Compositionally, the experimental formulations represented major changes in piroxicam particle size, level of filler, and level of sodium lauryl sulfate. Sixteen healthy volunteers received each formulation (20 mg) in a four-way crossover design. The three Maryland manufactured formulations were bioequivalent with the commercial product and were also bioequivalent among themselves. The major changes incorporated into these formulations did not result in major differences in bioavailability. The dissolution profiles which discriminated between the formulations in vitro did not accurately represent the in vivo bioavailability results. The results of this study are part of the research database that supports SUPAC-IR, an FDA guidance that provides relaxed testing and filing requirements for scale-up and post-approval changes to immediate-release oral solid dosage forms.

Adult↗
PubMed1998

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets.

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.

Adrenergic beta-Antagonists↗
PubMed1997

Evaluation of in vitro release rate and in vivo absorption characteristics of four metoprolol tartrate immediate-release tablet formulations.

The purpose of this investigation was to examine the impact of formulation and process changes on dissolution and bioavailability/bioequivalency of metoprolol tartrate tablets manufactured using a high-shear granulation process. A half-factorial (2(4-1), Res IV) design was undertaken to study the selected formulation and processing variables during scale-up. Levels and ranges for excipients and processing changes studied represented level 2 or greater changes as indicated by the SUPAC-IR Guidance. Blend and tableting properties were evaluated. Changes in sodium starch glycolate and magnesium stearate levels, and the order of addition microcrystalline cellulose (intra- vs. extragranular) were significant only in affecting percent drug released (Q) in 5, 10, and 15 min. Statistical analysis of data showed no significant curvature. No interaction effects were found to be statistically significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Subjects received four metoprolol treatments (Lopressor, slow-, medium-, and fast-dissolving formulations) separated by 1 week according to a randomized crossover design. After an overnight fast, subjects were administered one tablet (100 mg), blood samples were collected over 24 hr and plasma samples were analyzed. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that: (i) bioavailability/bioequivalency studies may not be necessary for metoprolol tartrate and perhaps other class 1 drugs after level 2 type changes and (ii) in vitro dissolution tests may be used to show bioequivalence of metoprolol formulations with processing or formulation changes within the specified level 2 ranges for the equipment examined.

Adrenergic beta-Antagonists↗
PubMed1996

Pharmacokinetics of dacarbazine in the regional perfusion of extremities with melanoma.

BACKGROUND: The pharmacokinetics of dacarbazine (DTIC), which has been shown to be an effective therapeutic agent against metastatic melanoma, has not been extensively studied. However, to improve the clinical use of the drug, more information on the kinetics is required. METHODS: A pharmacokinetic study was undertaken in six patients with melanoma of an extremity who were undergoing hyperthermic isolation perfusion with DTIC in order to understand better its clinical pharmacokinetics. Plasma was sampled from the arterial and venous lines of an extracorporeal pump during the perfusion with the systemic vein and urine sampled postperfusion. Samples were analyzed for DTIC. 2-azahypoxanthine (2-AZA), and aminoimidazole carboxamide (AIC). 99(m)Tc (Technetium) human serum albumin (HSA) was used in the perfusion circuit to monitor the crossover of the perfusate into the systemic circulation during the procedure. The data were analyzed using a compartmental model of sampled body compartments incorporating the isolated extremity. RESULTS: High tissue DTIC levels were maintained throughout the perfusion, whereas in the systemic circulation, plasma DTIC concentrations, when observed, were 40-100-fold less than those in the perfusate. Almost 70% of the DTIC administered was not recovered in the perfusate after the washout of the extremity. CONCLUSIONS: High levels of DTIC can be maintained in an extremity (i.e., arm or leg) during perfusion.

Antineoplastic Agents↗
PubMed1991

Update on the physical-chemical compatibility of cromolyn sodium nebulizer solution: bronchodilator inhalant solution admixtures.

Cromolyn sodium nebulizer solution, 1% (wt/vol), is physically and chemically compatible (stable) for at least 90 minutes when mixed in vitro with a new formulation (metabisulfite-free) of metaproterenol sulfate solution, an inhalant solution of albuterol sulfate or an atropine sulfate inhalant solution. Similarly, cromolyn sodium does not adversely affect the stability of the individual bronchodilator drugs in the admixtures. Since cromolyn sodium is compatible in admixtures with these bronchodilator drugs, adding these agents to cromolyn sodium nebulizer solution should have no negative influence on the effectively administered dose of either active ingredient.

Albuterol↗
PubMed1990

Pharmacologic profile of NPC 168 (naltrexone phenyl oxime), a novel compound with activity at opioid receptors.

NPC 168 (naltrexone phenyl oxime) was synthesized as a novel opioid antagonist and evaluated in several in vitro and in vivo assays. NPC 168 inhibited binding to the mu, delta and kappa subtypes of the opioid receptor with nanomolar potencies. The potency of NPC 168 to antagonize morphine-induced analgesia was slightly less than that of naltrexone and nalmefene following either intraperitoneal (ED50 = 0.07 mg/kg) or oral (ED50 = 0.82 mg/kg) administration. The duration of action of NPC 168 was approximately 8 hr following subcutaneous administration, compared to 4 hr for nalmefene, to antagonize oxymorphonazine-induced analgesia. The long duration of action of NPC 168 was substantiated by pharmacokinetic data that demonstrated rapid uptake and slow clearance of NPC 168 from brain. NPC 168 (5, 10 and 20 mg/kg) also inhibited cumulative 6-hr food intake in rats that were deprived of food for 24 hr, but chronic administration of this compound to rats over a three-week period resulted in a marginal reduction in cumulative body weight gain. NPC 168 at doses of up to 10 mg/kg did not produce a conditioned taste aversion. However, NPC 168 was slightly more toxic than either naltrexone or nalmefene when administered parenterally, and as toxic as nalmefene when administered by the oral route. These data demonstrate that NPC 168 is a novel opioid antagonist with a longer duration of action than either naltrexone or nalmefene.

Animals↗
PubMed1989

Cutaneous papillomatous hyperplasia in cyclosporine-A treated beagles.

All twelve Beagle dogs undergoing long-term therapy (26 weeks) with the immunosuppressive drug cyclosporine-A (30 mg/kg), developed cutaneous papillomatous hyperplasia. By week 7 all dogs developed generalized lesions distributed over the entire body. These occurred as irregular, oval, sessile, unpigmented, firm masses. The incidence and severity of the skin lesions varied among dogs and anatomic site, with no correlation to the blood level of cyclosporine. Microscopic analysis revealed that the epidermis formed short papillary folds on broad fibrovascular stalks and was hyperkeratotic and acanthotic. Mild hyperplasia of hair follicles and sebaceous glands was also evident. A mild diffuse infiltrate of lymphocytes and plasma cells was present in the papillary dermis. No histopathologic changes typical of papillomavirus infection were identified, nor were papillomavirus group-specific antigens or viral DNA detected. Other cutaneous side effects included hyperkeratosis of footpads, increased growth of hair and nails, and hyperkeratinization of the haired skin of the prepuce. All cutaneous lesions regressed spontaneously within 8 weeks following termination of cyclosporine administration. The hyperplastic lesions may have resulted from the action of cyclosporine via the T-lymphocyte system. Conversely a direct action of this drug on epithelial cells may have stimulated proliferation and keratinization.

Animals↗
PubMed1989

Cyclosporine-induced gingival overgrowth in beagle dogs.

Development of gingival overgrowth during daily long-term cyclosporine A treatment was studied in 2-yr-old beagles. Gingival enlargement developed in five of 12 dogs (42%), primarily in the mandibular anterior area. The earliest gingival changes occurred by 3 wk as an increase in the size of the interdental papillae. The lesions progressively became more severe, in some cases obscuring portions of teeth by wk 6. The redundant tissue exhibited an increase in connective tissue components and an inflammatory infiltrate primarily of plasma cells. Severity of the overgrowth varied in responding animals; both incidence and severity were related to the CSA concentration in blood. The mean CSA blood levels of responders were significantly greater than nonresponders at wk 3, 6 and 10. Since beagles develop gingival overgrowth similar to humans, they provide an excellent model to investigate the roles of local and systemic factors in the induction of gingival overgrowth.

Animals↗