Infectious Diseases

The Effect of CYP2B6 Genotype on the Clearance and Autoinduction of Efavirenz in Healthy Subjects and the Subsequent Impact on Efavirenz Exposure

Presented at ACoP 2024. Efavirenz is metabolized primarily by CYP2B6, to form 8-OH EFV, and also by CYP2A6, to form 7-OH EFV. Upon chronic administration, efavirenz induces both CYP2B6 and CYP2A6, leading to autoinduction of its metabolism. A population pharmacokinetic model was constructed to quantify the impact of CYP2B6 phenotype on efavirenz autoinduction and subsequent exposure.

Symbolic PBPK-PDE Modeling using Open-Source Julia Tools.

Presented at ACoP 2024. The poster introduces a framework for developing physiologically based pharmacokinetic (PBPK) models that incorporate partial differential equations (PDEs) to account for spatial drug distribution, using open-source Julia tools. This approach simplifies the integration of spatial components into PBPK models, demonstrated through a case study on naphthalene diffusion, and is applicable to various pharmacometric models requiring spatial considerations, such as topical, inhaled, and antitumor therapies.

A Quantitative Modeling and Simulation Framework to Support Candidate and Dose Selection of Anti-SARS-CoV-2 Monoclonal Antibodies to Advance Bamlanivimab Into a First-in-Human Clinical Trial

Neutralizing monoclonal antibodies (mAb) have emerged as promising therapeutics for COVID-19, with research efforts accelerated through open-access in silico models. Innovative approaches, including a physiologically-based pharmacokinetic (PBPK) model and a longitudinal SARS-CoV-2 viral dynamic model, facilitated the selection of optimal mAb candidate and therapeutic dose. By utilizing these models, the first-in-human trial of bamlanivimab (NCT04411628) initiated with a conservative dose of 700 mg, aiming to achieve maximum therapeutic effect while ensuring safety and tolerability.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda

Katherine Kay, Justin Goodwin, Hanna Ehrlich, Joyce Ou, Tracey Freeman, Kaicheng Wang, Fangyong Li, Martina Wade, Jonathan French, Liusheng Huang, Francesca Aweeka, Norah Mwebaza, Richard Kajubi, Matthew Riggs, Ana Ruiz-Garcia, Sunil Parikh. Clin Pharmacol Ther. Published online October 19, 2022. doi:10.1002/cpt.2768

Association of lumefantrine pharmacokinetics and resistance selection following artemether-lumefantrine treatment in children with and without HIV in Uganda

Katherine Kay, Justin Goodwin, Hanna Ehrlich, Joyce Ou, Tracy Freeman, Kaicheng Wang, Fangyong Li, Martina Wade, Jonathan French, Liusheng Huang, Francesca T. Aweeka, Norah Mwebaza, Richard Kajubi, Matthew Riggs, Ana Ruiz-Garcia, Sunil Parikh. Poster presented at American Society of Tropical Medicine and Hygiene (ASTMH). October 30 – November 3, 2022. Poster #1434.

A physiologically-based pharmacokinetic modeling approach to support candidate and first in human dose selection for bamlanivimab

Tim Knab, Ahmed Elmokadem, Emmanuel Chigutsa, Eric Jordie, Matthew Riggs, Patricia Brown-Augsburger, Christopher Wiethoff, Ajay Nirula, Jenny Y Chien, Lisa O’Brien.  Poster presented at Population Approach Group Europe Annual Meeting; 2-3 and 6-7 September 2021.  Poster I-64.

Should Deep-Sequenced Amplicons Become the New Gold Standard for Analyzing Malaria Drug Clinical Trials?

Jones S, Kay K, Hodel EM, Gruenberg M, Lerch A, Felger I, Hastings I. Antimicrobial Agents and Chemotherapy. 2021;65(10), e0043721. doi:10.1128/AAC.00437-21

Pharmacokinetic and Pharmacodynamic Target Attainment in Adult and Pediatric Patients Following Administration of Ceftaroline Fosamil as a 5-Minute Infusion

 

Riccobene TA, Carrothers TJ, Knebel W, Raber S, Chan PLS. Clin Pharmacol Drug Dev. 2021 Apr;10(4):420-427. doi: 10.1002/cpdd.907.

Incorporating genetic selection into individual‐based models of malaria and other infectious diseases

Hastings, IM, Hardy, D, Kay, K, Sharma, R. Evol Appl. 2020; 13: 2723– 2739.

Modeling and simulation of lumefantrine pharmacokinetics in HIV-infected and HIV-uninfected children with malaria and the role of lumefantrine exposure as a potential driver of drug resistance

Kay K, Goodwin J, Mwebaza N, Ruiz A, Ehrlich H, Ou J, Freeman T, Wade M, Huang L, Wang K, Li F, Aweeka FT, Riggs M, Kajubi R, Parikh S.  Presented at the annual meeting of the American Society of Tropical Medicine and Hygiene, October 16-18, 2020.

Improving Methods for Analyzing Antimalarial Drug Efficacy Trials: Molecular Correction Based on Length-Polymorphic Markers msp-1, msp-2, and glurp

Presentation by Katherine Kay Ph.D at R/Medicine. Boston, MA. 14 September 2019.

 

Population PK modeling and target attainment simulations to support dosing of ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia

Riccobene TA, Khariton T, Knebel W, Das S, Li J, Jandourek A, Carrothers TJ, Bradley JS.  The Journal of Clinical Pharmacology, March 2017; 57: 345–355. doi: 10.1002/jcph.809

Animal-to-human dose translation of obiltoxaximab for treatment of inhalational anthrax under the US FDA animal rule.

Nagy CF, Mondick J, Serbina N, Casey LS, Carpenter SE, French J, Guttendorf R.  Clinical And Translational Science, 2016 Dec; 10: 12–19.

Efficacy projection of obiltoxaximab for treatment of inhalational anthrax across a range of disease severity

Yamamoto BJ, Shadiack AM, Carpenter S, Sanford D, Henning LN, O’Connor E, Gonzales N, Mondick J, French J, Stark GV, Fisher AC, Casey LS, Serbina NV. Antimicrob Agents Chemother 60:5787–5795. doi:10.1128/AAC.00972-16

Penetration of ceftaroline into the epithelial lining fluid of healthy adult subjects

Riccobene TA, Pushkin R, Jandourek A, Knebel W, Khariton T.  Antimicrob Agents Chemother. 2016 Sep 23;60(10):5849-57.

Zika microcephaly cutoffs revisited: A study of Non-parametric methods in fetal growth

Wilbur JD, Ohuma E, Xiao L, Mouksassi S, Hafen R.  Presented at the Annual Meeting of the Population Approach Group in Europe (PAGE), Lisboa, June 2016.

Pharmacokinetic modeling of the relationship between sustained virological response and plasma concentrations of faldaprevir or bi-207127 in hcv gt1-infected patients in sound-c2

Olson S, Baron K, Riggs M, Bocher WO, Mensa FJ.  Journal of Hepatology, 58:S492–S493.

Population pharmacokinetics and exposure-response of albinterferon alfa-2b

Riggs MM, Bergsma TT, Rogers JA, Gastonguay MR, Subramanian GM, Chen C, Devalaraja M, Corey AE, Sun H, Yu J, and Stein DS. The Journal of Clinical Pharmacology, 52: 475–486, April 2012. doi:10.1177/0091270011399576

Attenuation of vancomycin pharmacodynamics (PD) due to dense inoculum methicillin-resistant Staphylococcus aureus (MRSA)

Johnston CK, Tsuji BT.  Presented at the American College of Clinical Pharmacy (ACCP) Annual Meeting; October 2011; Pittsburgh, PA.

Evaluation of rapid and sustained population viral response rates predicted under hepatitis C viral dynamic models

Baron KT, Ravva P, Purohit V, Riggs MM, Gastonguay MR. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 2011.