Geraldine M. Ferron
University at Buffalo
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Clinical Pharmacology & Therapeutics | 1997
Geraldine M. Ferron; Elena V. Mishina; James J. Zimmerman; William J. Jusko
To characterize the dose‐related pharmacokinetics of the immunosuppressant agent sirolimus (formerly rapamycin) in kidney transplant patients by use of two‐stage and nonlinear mixed‐effect model population methods.
Analytical Biochemistry | 2003
Lilian G. Yengi; Qian Xiang; Jinmei Pan; John Kao; Simon E. Ball; Richard J. Fruncillo; Geraldine M. Ferron; C. Roland Wolf
There is considerable interindividual variation in mans ability to metabolize drugs and foreign compounds. These differences can partly be attributed to genetic polymorphisms that result in the generation of multiple phenotypes with different drug-metabolizing capabilities. Genetically derived differences can easily be assessed by genotyping assays in cases where the polymorphism has been identified. However, many of the polymorphisms that result in these are not known, secondly not all the differences can be attributed to genetic polymorphisms, hence genotyping methods cannot be employed. We have therefore, developed real-time (Taqman) PCR assays to quantitate levels of P450 mRNAs in human tissues. These assays are highly sensitive, reproducible, and specific and will allow quantitation of P450 mRNA levels in various human tissues. We have applied these assays to quantitate cytochrome P450 mRNA levels in human skin samples from 27 healthy volunteers. The expression of 13 P450s was assessed. The major enzymes detected were CYP1B1, CYP2B6, CYP2D6, and CYP3A4 with mean values of 2.5, 2.6, 2.7, and 1.1 fg/18S rRNA in 50ng total RNA, respectively. Lower levels of CYP2C18, CYP2C19, and CYP3A5 were also detected while CYP1A2, 2A6, and 2C8 were below limits of detection. There was interindividual variation in the levels of mRNA among the 27 subjects studied although Poisson analysis showed data to be normally distributed, except for CYP2B6, as some individuals completely lacked CYP2B6 mRNA.
The Journal of Clinical Pharmacology | 2002
Geraldine M. Ferron; Jeffrey Paul; Richard J. Fruncillo; Lyette S Richards; Norbert Knebel; John Getsy; Steven M. Troy
Retigabine, a first‐in‐class selective M‐current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo‐controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half‐life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabines pharmacokinetics was linearly dose proportional. Steady‐state pharmacokinetics was in agreement with single‐dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21‐360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed‐dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.
The Journal of Clinical Pharmacology | 1999
James J. Zimmerman; Geraldine M. Ferron; Heng‐Keang Lim; Vernon D. Parker
The bioavailability of an oral nonaqueous solution of sirolimus was compared under fasting conditions and after a high‐fat meal in a randomized, two‐way crossover pharmacokinetic study. Healthy volunteers were administered a 15 mg single dose of sirolimus on two occasions, once while fasting and once after consumption of a high‐fat breakfast. Whole blood concentrations of sirolimus were assayed by using a validated method with high‐performance liquid chromatography/tandem mass spectrometric detection. Sirolimus was absorbed more slowly when administered after a high‐fat meal than when administered after fasting, as shown by statistically significant reductions in peak concentration (Cmax) and the ratio of Cmax to the area under the curve (AUC), and lengthening of the time to peak concentration. The oral availability of sirolimus was increased to a modest extent (35%) and in a uniform manner when administered with a high‐fat meal; the geometric mean ratio of the fed/fasting AUC values was 1.35, with a 90% confidence interval of 1.26 to 1.46. Food had no effect on the terminal half‐life of sirolimus (mean values of 67 to 68 hours). The 35% increase in AUC obtained after a high‐fat meal appears small relative to the intersubject and intra‐subject variabilities observed in clinical trials. However, to minimize unnecessary fluctuations in trough whole blood sirolimus concentrations, it is advisable that sirolimus be administered consistently in individual patients, either with or without meals.
The Journal of Clinical Pharmacology | 1996
Geraldine M. Ferron; Myriam Rochdi; William J. Jusko; Jean-Michel Scherrmann
Colchicine is an antimitotic drug used to treat gout and familial Mediterranean fever. Absolute bioavailability, pharmacokinetics, and absorption characteristics of colchicine after single 1.0‐mg doses in oral solution or tablet form or 0.5‐mg intravenous doses were compared in 6 subjects. This study was combined with 14 days of multiple‐dose administration of 1.0‐mg colchicine tablets in 6 subjects. Serial blood samples were collected for 48 hours after administration of single doses and for 120 hours after the last dose in the multiple‐dose regimen. Plasma colchicine profiles as measured by radioimmunoassay were analyzed using deconvolution and compartmental methods. After intravenous bolus injection of colchicine, the area under the concentration‐time curve (AUC) was 61.2 ± 12.7 ng · hr/mL, steady‐state volume of distribution (V88) was 419 ± 95 L, systemic clearance (Cl) was 8.5 ± 1.8 L/hr, and the terminal half‐life (t1/2) was 57.8 ± 10.7 hours. After oral administration in solution form, peak plasma concentrations (Cmax) of 6.50 ± 1.03 ng/mL were reached at time (tmax) 1.07 ± 0.55 hours, with a rate of 0.109 ± 0.024 hr−1 (Cmax/AUC); bioavailability was 47 ± 14%. Oral tablets yielded similar Cmax, tmax, and Cmax/AUC values, but AUC was significantly lower. Most participants exhibited a secondary peak within 6 hours of administration, possibly in relation to a second absorption site or enterohepatic recirculation. This second absorption process was significantly longer than the first one, and accounted for a similar amount of colchicine absorbed. From the multiple‐dose study, a model including an alteration of colchicine absorption due to possible drug‐induced gastrointestinal modifications allowed better determination of steady‐state plasma concentrations of colchicine.
Clinical Pharmacology & Therapeutics | 2003
Robert Hermann; Geraldine M. Ferron; Katharina Erb; Norbert Knebel; Peter Ruus; Jeffrey Paul; Lyette S Richards; Hans‐Peter Cnota; Steven M. Troy
The novel antiepileptic drug retigabine is the first selective M‐current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N‐glucuronidation, acetylation) exclusively and renal excretion.
The Journal of Clinical Pharmacology | 1996
William J. Jusko; Geraldine M. Ferron; Suzette M. Mis; Barry D. Kahan; James J. Zimmerman
The pharmacokinetic interaction of multiple oral doses of sirolimus (rapamycin) and prednisone were evaluated in 40 stable patients with renal transplants receiving concomitant multiple doses of cyclosporine. Nine sirolimus dosage levels from 1 mg/m2/ day to 13 mg/m2/day were studied and compared with placebo. Plasma concentrations of prednisone, prednisolone, and cortisol were measured by high‐performance liquid chromatography and analyzed by noncompartmental methods. Mean pharmacokinetic values of prednisolone found before sirolimus administration were as follows: peak plasma concentration (Cmax) was 187 ng/mL; time to peak plasma concentration (tmax) was 2.03 hours; rate of reaching peak plasma concentration (Cmax divided by the area under the concentration‐time curve [AUC]) was 0.149 hour−1; terminal half‐life (t1/2) was 3.60 hours; AUC was 1206 ng · hour/mL; and apparent clearance (Cl/F) was 0.094 L/hour/kg. During the 2 weeks of concomitant administration, prednisolone elimination decreased in relation to sirolimus dosages. These changes were modest, with mean increases of 18% in Cmax and 27% in t1/2 and mean decreases of 27% in Cl/F for the groups receiving 6 mg/m2/day to 13 mg/m2/day. Most patients initially had plasma cortisol concentrations indicative of adrenal suppression. With sirolimus treatment, the Cmax of cortisol did not decrease further, but the AUC (8:00 am‐8.00 pm) values were significantly lower, independent of sirolimus exposure. The AUC for cyclosporine did not correlate with sirolimus and prednisolone exposure. A 2‐week course of sirolimus showed a slight pharmacokinetic interaction between sirolimus and prednisolone/prednisone/cortisol in stable patients with renal transplants.
Clinical Therapeutics | 2001
Geraldine M. Ferron; Richard A. Preston; Robert J. Noveck; Paul J. Pockros; Philip R. Mayer; John Getsy; Marybeth Turner; Madelyn Abell; Jeffrey Paul
BACKGROUND Patients with impaired hepatic function usually require gastric acid-suppressant therapy but are at increased risk for drug interactions and may require dosage adjustments. The proton pump inhibitor pantoprazole is rapidly absorbed and eliminated, primarily by cytochrome P450 (CYP) 2C19 isozymes. OBJECTIVE This study sought to determine whether dosage adjustment of pantoprazole is required in patients with moderate or severe hepatic impairment by comparing the pharmacokinetic profile of pantoprazole in such patients with that in healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. METHODS Patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment received oral pantoprazole 40 mg once daily on days 1 through 4 and then on alternate days (days 6 and 8). Serial blood samples were collected on days 4 and 8 for analyses of plasma pantoprazole concentrations. Pharmacokinetic data were compared between the 2 groups with hepatic impairment and against historical data from 17 healthy subjects who were genetically slow CYP2C19 metabolizers of pantoprazole. RESULTS Twenty-two patients participated in the study, 13 in the Child-Pugh class B group and 9 in the Child-Pugh class C group. No clinically significant differences in pantoprazole pharmacokinetics were noted between the patients with hepatic impairment and the healthy slow metabolizers of pantoprazole on days 4 and 8. Pantoprazole was well tolerated. Four Child-Pugh class B patients and 3 Child-Pugh class C patients reported > or = 1 adverse event. Adverse events were generally mild or moderate, and were similar to those reported in healthy subjects. Two patients discontinued the study because of severe events related to their underlying disease. CONCLUSIONS The pharmacokinetics and tolerability of pantoprazole were similar in patients with moderate hepatic impairment, patients with severe hepatic impairment, and healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. Thus, no dosage adjustment of pantoprazole is required in patients with hepatic impairment, regardless of its severity. However, caution should be exercised when giving pantoprazole to patients with severe hepatic impairment.
The Journal of Clinical Pharmacology | 2001
Geraldine M. Ferron; William McKeand; Philip R. Mayer
The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, IV) and 22 healthy volunteers (10 to 80 mg, IV and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after IV administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half‐lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h‐1 and 0.031 h‐1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of IV and oral pantoprazole on gastric secretion and maybe used to predict effects under other dosage regimens.
Transplantation | 1998
Geraldine M. Ferron; Nancy A. Pyszczynski; William J. Jusko
BACKGROUND Cyclosporine (CsA), prednisolone (Pred), and sirolimus (Sir) are immunosuppressive compounds inhibiting lymphocyte proliferation at the cytokine gene transcription (CsA and Pred) or signal transduction (Sir) levels. METHODS Double- and triple-drug interactions were simultaneously studied using lectin-induced proliferation of isolated cell lymphocytes (ICLP) and whole blood lymphocytes from men and women as well as two-way mixed lymphocyte reaction assays. Drug interactions were described with isobolograms and quantitated with the universal response surface approach by estimating the interaction parameter alpha. RESULTS All compounds inhibited more than 89% of control proliferative responses. In each assay, CsA was less potent than Pred (3- to 14-fold) and Sir (5- to 11-fold). Sir was of similar or higher potency than Pred and 1.5-fold more potent in men than women. Pred was 1.4 times more potent in women but this was found only in the ICLP assay. All combinations were synergistic (alpha>0), with greater synergism found for combinations involving Sir, especially in the ICLP (alpha>13) and two-way mixed lymphocyte reaction (alpha>40) assays. Moreover, the Sir/Pred interaction in the ICLP assay was two to five times more synergistic in women, because their mean alpha was 56 compared with 13 in men. Double-combination alpha values were able to reasonably describe CsA/Pred/Sir triple-interaction effects. CONCLUSIONS These studies indicate that CsA, Pred, and Sir act and synergistically interact in vitro, with gender and assay as additional factors, and that whole blood lymphocyte proliferation cultures are useful in assessing the nature and intensity of drug interactions.