Publications by authors named "Thomas Peppard"

9 Publications

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Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

J Pharmacokinet Pharmacodyn 2021 Jun 5;48(3):411-438. Epub 2021 May 5.

School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, NY, USA.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC/SC to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.
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http://dx.doi.org/10.1007/s10928-021-09755-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099395PMC
June 2021

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.

J Pharmacokinet Pharmacodyn 2021 Apr 3;48(2):261-272. Epub 2021 Jan 3.

School of Pharmacy and Pharmaceutical Sciences, State University of New York, University of Buffalo, Buffalo, NY, USA.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability [Formula: see text]. The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ([Formula: see text] of 9.29 L/h, steady-state volume ([Formula: see text] of 56.4 L, IM absorption constant [Formula: see text] of 0.460 1/h and oral absorption constant ([Formula: see text] of 0.936 1/h. Betamethasone parameters were CL/F of 5.95 L/h, [Formula: see text] of 72.4 L, [Formula: see text] of 0.971 1/h, and [Formula: see text] of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.
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http://dx.doi.org/10.1007/s10928-020-09730-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778726PMC
April 2021

Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response.

EJNMMI Res 2020 Feb 10;10(1). Epub 2020 Feb 10.

Department of Science and Technology/National Research Foundation, Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research, Cape Town, South Africa.

Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes.

Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions.

Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
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http://dx.doi.org/10.1186/s13550-020-0591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010890PMC
February 2020

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India.

Clin Transl Sci 2020 03 13;13(2):391-399. Epub 2019 Dec 13.

State University of New York, School of Pharmacy and Pharmaceutical Sciences, University of Buffalo, Buffalo, New York, USA.

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery.
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http://dx.doi.org/10.1111/cts.12724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070803PMC
March 2020

Bacterial Loads Measured by the Xpert MTB/RIF Assay as Markers of Culture Conversion and Bacteriological Cure in Pulmonary TB.

PLoS One 2016 10;11(8):e0160062. Epub 2016 Aug 10.

Division of Infectious Diseases, Rutgers New Jersey Medical School, ^Rutgers Biomedical & Health Sciences (Formerly UMDNJ), 185 South Orange Avenue, Newark, New Jersey, United States of America.

Introduction: Biomarkers are needed to monitor tuberculosis (TB) treatment and predict treatment outcomes. We evaluated the Xpert MTB/RIF (Xpert) assay as a biomarker for TB treatment during and at the end of the 24 weeks therapy.

Methods: Sputum from 108 HIV-negative, culture-positive pulmonary TB patients was analyzed using Xpert at time points before and during anti-TB therapy. Results were compared against culture. Direct Xpert cycle-threshold (Ct), a change in the Ct (delta Ct), or a novel "percent closing of baseline Ct deficit" (percent closing) were evaluated as classifiers of same-day and end-of-treatment culture and therapeutic outcomes.

Results: Xpert was positive in 29/95 (30.5%) of subjects at week 24; and positive one year after treatment in 8/64 (12.5%) successfully-treated patients who remained free of tuberculosis. We identified a relationship between initial bacterial load measured by baseline Xpert Ct and time to culture conversion (hazard ratio 1.06, p = 0.0023), and to the likelihood of being among the 8 treatment failures at week 24 (AUC = 72.8%). Xpert Ct was even more strongly associated with culture conversion on the day the test was performed with AUCs 96.7%, 99.2%, 86.0% and 90.2%, at Day 7, Week 4, 8 and 24, respectively. Compared to baseline Ct measures alone, a combined measure of baseline Ct plus either Delta Ct or percent closing improved the classification of treatment failure status to a 75% sensitivity and 88.9% specificity.

Conclusions: Genome loads measured by Xpert provide a potentially-useful biomarker for classifying same day culture status and predicting response to therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160062PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980126PMC
August 2017

Early Biomarkers and Regulatory Innovation in Multidrug-Resistant Tuberculosis.

Clin Infect Dis 2015 Oct;61Suppl 3:S160-3

Certara, LP, St Louis, Missouri.

Biomarkers play an essential role in accelerating drug development. Sputum culture conversion using solid medium is the best-characterized tuberculosis biomarker, having been examined at the patient and trial levels in studies with thousands of subjects, and having recently been validated using data from 3 unsuccessful phase 3 trials. We presently are poised at the threshold of regulatory innovation for antibacterials to treat drug-resistant infections, in which Special Medical Use authorization restricted to patients with limited options could be based on the results of small clinical trials. Patients worldwide would be well served by licensing of new regimens for multidrug-resistant tuberculosis based on biomarker evidence commensurate with the urgency of the current global crisis.
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http://dx.doi.org/10.1093/cid/civ612DOI Listing
October 2015

Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update.

PLoS One 2015 29;10(4):e0125403. Epub 2015 Apr 29.

Certara, LP, St. Louis, Missouri, United States of America.

Background: New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.

Methods: Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.

Findings: The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.

Interpretation: Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125403PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414505PMC
January 2016

Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension.

J Clin Hypertens (Greenwich) 2013 Mar 14;15(3):186-92. Epub 2012 Dec 14.

A Medical Corporation, Beverly Hills, CA, USA.

Aldosterone inhibition with mineralcorticoid receptor antagonists (MRAs) is an effective treatment for resistant hypertension. Aldosterone synthase inhibitors (ASIs) are currently being investigated as a new therapeutic strategy to reduce aldosterone secretion from the adrenal gland. In this study, the efficacy and safety of the first-generation ASI LCI699 (0.25 mg twice daily, 1 mg 4 once daily, and 0.5 mg/1 mg twice daily) was compared with placebo and eplerenone (50 mg twice daily), in patients with resistant hypertension. Placebo-adjusted decreases in systolic blood pressure (BP) with LCI699 ranged from 2.6 mm Hg to 4.3 mm Hg at week 8; changes in diastolic BP ranged from +0.3 mm Hg to -1.2 mm Hg. However, reductions were smaller than observed with eplerenone 50 mg twice daily (9.9 mm Hg and 2.9 mm Hg for systolic and diastolic BP, respectively) and not statistically significant vs placebo. LCI699 suppressed plasma aldosterone levels in a dose-related manner with corresponding dose-dependent increases in plasma renin activity and plasma 11-deoxycorticosterone. LCI699 and eplerenone were well tolerated. These data demonstrate that aldosterone synthesis inhibition with LCI699 lowers BP modestly in patients with resistant hypertension. Aldosterone synthesis inhibition might offer an attractive adjunct to aldosterone receptor blockade, although the potential of a combination MRA/ASI has not yet been tested.
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http://dx.doi.org/10.1111/jch.12051DOI Listing
March 2013

The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study.

J Clin Hypertens (Greenwich) 2012 Sep 7;14(9):580-7. Epub 2012 Jun 7.

Encode Clinic, Reykjavik, Iceland.

Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.
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http://dx.doi.org/10.1111/j.1751-7176.2012.00667.xDOI Listing
September 2012