Lawrence Fleckenstein

Lawrence Fleckenstein

Office

S427

Phone

(319) 335-8804

Research Narrative

Dr. Fleckenstein’s long-term research focus has been in clinical pharmacokinetics and pharmacodynamics (PK/PD), particularly as these disciplines relate to the influence of disease states or population factors on the variability and elimination of drugs from the human body. Traditional and population pharmacokinetics models and modeling form an increasing part of the approach to the optimal design, development and use of new medicines. While models to characterize the pharmacokinetics of drugs take on many forms, one of the most powerful and useful approaches is to integrate patient demographic, pathophysiologic and therapeutic features to investigate alteration of dose-concentration relationships. Population pharmacokinetics seeks to identify pathophysiologic factors that cause changes in the dose-concentration relationship so that if such changes are associated with clinically significant shifts in the therapeutic index, the dosage can be appropriately adjusted. Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations between and within individuals representative of those in whom the drug will be used clinically.

Dr Fleckenstein’s research interests include:
1.Design of clinical pharmacokinetic experiments, population PK/PD study design and clinical trial design
2.The use of traditional and population methods for PK/PD analysis.
3.The influence of disease factors on the pharmacokinetics of drugs.

Dr. Fleckenstein’s current research program is focused on the pharmacokinetics and development of new therapies for parasitic diseases for underdeveloped countries, primarily malaria, and onchocerciasis. These studies involve quantitation of drug levels of investigational new drugs in biological fluids by HPLC or LCMS analysis and subsequent PK/PD analysis using traditional and population approaches.

Curriculum vitae

Education
Doctor of Pharmacy, University of California, School of Pharmacy, San Francisco, CA, 1972
Bachelor of Arts, Botany, University of California, Berkeley, CA, 1968

Professional Experience
Professor, Division of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Iowa, Iowa City, IA, 1991-Present
Acting Chief, Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research (WRAIR), Washington, DC, 1988-1991
Supervisory Pharmacologist, Department of Pharmacology, WRAIR, Washington, DC, 1986-1988
Adjunct Associate Professor, Department of Pharmacology (Primary), Associate Research Professor, Department of Medicine (Secondary), Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD, 1982-1991
Assistant Professor, Department of Pharmacology, USUHS, Bethesda, MD, 1980-1982
Research Pharmacologist, Department of Pharmacology, WRAIR, Washington, DC, 1979-1986
Assistant Professor (Clinical), School of Pharmacy,University of California, San Francisco, CA, 1975-1979
Director, Drug Information Service, Alta Bates Hospital, Berkeley, CA, 1975-1979
Instructor of Pharmacology and Toxicology, Department of Pharmacology, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 1972-1975

Honors and Awards 
Leadership Appreciation Award – Medicines for Malaria Venture & Shin Poong Pharmaceuticals, 2012
Medicines for Malaria Venture Project of the Year – Award to pyronaridine-artesunate project team, 2005
Elected AAAS Fellow, 1995
Outstanding Service Medal, USUHS, 1991
Commander's Award for Civilian Service, WRAIR, 1989
U.S. Army Research and Development Award, 1989

Representative Publications
Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, Fleckenstein L. Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J. 12:70, 2013.

Rutteman GR, Erich SA, Mol JA, Spee B, Grinwis GC, Fleckenstein L, London CA, Efferth T. Safety and efficacy field study of artesunate for dogs with non-resectable tumours. Anticancer Res. 33(5):1819-27, 2013.

Kayentao K, Doumbo OK, Pénali LK, Offianan AT, Bhatt KM, Kimani J, Tshefu AK, Kokolomami JH, Ramharter M, de Salazar PM, Tiono AB, Ouédraogo A, Bustos MD, Quicho F, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malar J. 11:364, 2012.

Croft SL, Duparc S, Arbe-Barnes SJ, Craft JC, Shin CS, Fleckenstein L, Borghini-Fuhrer I, Rim HJ. Review of pyronaridine anti-malarial properties and product characteristics. Malar J. 11:270, 2012.

Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, Pénali LK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine–Artesunate Study Team. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med. 366(14):1298-309, 2012.

Morris CA, Lopez-Lazaro L, Jung D, Methaneethorn J, Duparc S, Borghini-Fuhrer I, Pokorny R, Shin CS, Fleckenstein L. Drug-drug interaction analysis of pyronaridine/artesunate and ritonavir in healthy volunteers. Am J Trop Med Hyg. 86(3):489-95, 2012.

Korth-Bradley JM, Parks V, Chalon S, Gourley I, Matschke K, Cailleux K, Fitoussi S, Fleckenstein L. The effect of a high-fat breakfast on the pharmacokinetics of moxidectin in healthy male subjects: a randomized phase I trial. Am J Trop Med Hyg. 86(1):122-5, 2012.

Morris D, Podolski J, Kirsch A, Wiehle R, Fleckenstein L. Population pharmacokinetics of telapristone (CDB-4124) and its active monodemethylated metabolite CDB-4453, with a mixture model for total clearance. AAPS J. 13(4):665-73, 2011.

Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, Fleckenstein L. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J. 10:263, 2011.

Korth-Bradley JM, Parks V, Chalon S, Gourley I, Matschke K, Gossart S, Bryson P, Fleckenstein L. Excretion of moxidectin into breast milk and pharmacokinetics in healthy lactating women. Antimicrob Agents Chemother. 55(11):5200-4, 2011.

Morris CA, Onyamboko MA, Capparelli E, Koch MA, Atibu J, Lokomba V, Douoguih M, Hemingway-Foday J, Wesche D, Ryder RW, Bose C, Wright L, Tshefu AK, Meshnick S, Fleckenstein L. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria. Malar J. 10:114, 2011.

Onyamboko MA, Meshnick SR, Fleckenstein L, Koch MA, Atibu J, Lokomba V, Douoguih M, Hemingway-Foday J, Wesche D, Ryder RW, Bose C, Wright LL, Tshefu AK, Capparelli EV. Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC. Malar J. 10:49, 2011.

Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, Rao BH, Tjitra E, Purnama A, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS One. 6(1):e14501, 2011.

Fusco DN, Downs JA, Satlin MJ, Pahuja M, Ramos L, Barie PS, Fleckenstein L, Murray HW. Non-oral treatment with ivermectin for disseminated strongyloidiasis. Am J Trop Med Hyg. 83(4):879-83, 2010.

Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra E, Bedu-Addo G, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine-artesunate Study Team. Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet. 375(9724):1457-67, 2010.

Grein JD, Mathisen GE, Donovan S, Fleckenstein L. Serum ivermectin levels after enteral and subcutaneous administration for Strongyloides hyperinfection: a case report. Scand J Infect Dis. 42(3):234-6, 2010.

Tan B, Naik H, Jang IJ, Yu KS, Kirsch LE, Shin CS, Craft JC, Fleckenstein L. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects. Malar J. 8:304, 2009.

Harirforoosh S, Fleckenstein L, Mahajan P, Aruoma OI, Huang Y, Moridani M. The importance of including topics related to pharmacogenetics, pharmacogenomics, and medical genetics in the pharmacy curriculum. Am J Pharm Educ. 3(6):114, 2009.

Moridani M, Maitland-van der Zee AH, Sasaki H, McKinnon R, Fleckenstein L, Shah VP. AAPS-FIP summary workshop report: Pharmacogenetics in individualized medicine: methods, regulatory, and clinical applications. AAPS J. 11(2):214-6, 2009.

Rose CE, Paciullo CA, Kelly DR, Dougherty MJ, Fleckenstein L. Fatal Outcome of Disseminated Strongyloidiasis despite Detectable Plasma and Cerebrospinal Levels of Orally Administered Ivermectin. J Parasitol Res. 2009, 2009.

Dec Bronsvoort BM, Makepeace BL, Renz A, Tanya VN, Fleckenstein L, Ekale D,Trees AJ. UMF-078: A modified flubendazole with potent macrofilaricidal activity against Onchocerca ochengi in African cattle. Parasit Vectors. 1(1):18, 2008.

Ramharter M, Kurth F, Schreier AC, Nemeth J, Glasenapp Iv, Bélard S, Schlie M,Kammer J, Koumba PK, Cisse B, Mordmüller B, Lell B, Issifou S, Oeuvray C, Fleckenstein L, Kremsner PG. Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. J Infect Dis. 198(6):911-9, 2008.

Naik H, Wei SY, Schmidt MS, Murry DJ, Fleckenstein L, Development and Validation of a Liquid Chromatography-Mass Spectrometry Assay for the Determination of Pyronaridine in Human Urine.  J. Chromato. B. Biomedical Applications 853:80-87, 2007.

Al-Azzam S, Fleckenstein L, Cheng C, Dzimianski MT, McCall JW. Comparison of the Pharmacokinetics of Moxidectin and Ivermectin after Oral Administration to Beagle Dogs. Biopharm. Drug Disp. 28:431-8, 2007.

Naik H, Imming PY, Schmidt MS, Murry DJ, Fleckenstein L, Development and Validation of a Liquid Chromatography-Mass Spectrometry Assay for the Determination of Pyronaridine in Human Blood for Application to Clinical Pharmacokinetic Studies.  J. Pharm. Biomed. Anal. 45 112-9, 2007. 

Kitzman D, Wei SY, Fleckenstein L, Liquid Chromatographic Assay of Ivermectin in Human Plasma for Application to Clinical Pharmacokinetic Studies. J. Pharm. Biomed. Anal., 40:1013-20, 2006.

Turner SA, Maclean JD, Fleckenstein L, and Greenaway C, Parenteral administration of ivermectin in a patient with disseminated strongyloidiasis, Amer. J. Trop. Med. Hyg. 73:911-914, 2005.

Marty FM, Lowry CM, Rodriguez M, Milner DA, Pieciak WS, Sinh, A, Fleckenstein L, Baden LR, Treatment of human disseminated strongyloidiasis with a parenteral veterinary formulation of ivermectin. Clin. Inf. Dis. 41:e5-8, 2005.

Naik H, Murry DJ, Kirsch LE, Fleckenstein L, Development and validation of a high-performance liquid chromatography-mass spectroscopy assay for determination of artesunate and dihydroartemisinin in human plasma. J. Chromato. B. Biomedical Applications, 816:233-242, 2005.

Kshirsagar NA, Gogtay NJ, Garg BS, Deshmukh PR, Rajgor DD, Kadam VS, Kirodian BG, Ingole NS, Mehendale AM, Fleckenstein L, Karbwang J, Lazdins-Helds JK, Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India. Transactions of the Royal Society of Tropical Medicine & Hygiene. 98(4):205-217, 2004 Apr

Cotreau MM, Warren S, Ryan JL, Fleckenstein L, Vanapalli SR, Brown KR, Rock D, Chen CY, Schwertschlag US, The antiparasitic moxidectin: Safety, tolerability, and pharmacokinetics in humans. Journal of Clinical Pharmacology. 43(10):1108-1115, 2003 Oct.

Shenoy RK, Suma TK, John A, Arun SR, Kumaraswami V, Fleckenstein L, Na- Bangchang K, The pharmacokinetics, safety and tolerability of the co-administration of diethylcarbamazine and albendazole. Annals of Tropical Medicine & Parasitology. 96(6):603-614, 2002.

Vanapalli SR, Hung YP, Fleckenstein L, Dzimianski MT, McCall JW, Pharmacokinetics and dose proportionality of oral moxidectin in beagle dogs. Biopharm. Drug Dispos. 23:263-272, 2002.

Kitzman D, Cheng KJ, Fleckenstein L, HPLC assay for albendazole and metabolites in human plasma for clinical pharmacokinetic studies. J. Pharm. Biomed. Anal., 30:801-813, 2002.

Chen Y, Fleckenstein L, Assay method for the determination of moxidectin in plasma by high-performance liquid chromatography for application to clinical pharmacokinetic studies. J. Pharm. Biomed. Anal. 29:917-926, 2002.

Miller JR, Fleckenstein L, Gas chromatographic assay of diethylcarbamazine in human plama for aplication to clinical pharmacokinetic studies. J. Pharm. Biomed. Anal. 26:667-676, 2001.

Chen Y, Fleckenstein L, Improved assay method for the determination of pyronaridine in plasma and whole blood by high-performance liquid chromatography for application to clinical pharmacokinetic studies. J. Chromato. B. Biomedical Applications 752:39-46, 2001.

Theplertboon R, Fleckenstein L, Dzimianski MT, McCall JW, Pharmacokinetics of UMF-078, a candidate antifilarial drug, in infected dogs. Amer. J. Trop. Med. Hyg. 62:86-91, 2000.