Quantitative prediction of human clearance guiding the development of Raltegravir (MK-0518, isentress) and related HIV integrase inhibitors

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Ralph LauferMichael Rowley

Abstract

Human HIV integrase inhibitors are a novel class of antiretroviral drugs that act by blocking incorporation of the proviral DNA into the host cell genome, a crucial step in the life cycle of HIV. In the present work, quantitative methods for prediction of human pharmacokinetics were used to guide the selection of development candidates from a series of dihydroxypyrimidine and N-methylpyrimidinone carboxamide inhibitors of HIV integrase, which are cleared mainly by O-glucuronidation. The pharmacokinetics of 10 drugs from this series was determined in several preclinical species, including rats, dogs, rhesus monkeys, and rabbits, and the in vitro turnover, plasma protein binding, and blood/plasma partition ratio were studied using preparations from both preclinical species and humans. Two clearance prediction methods, based on physiologically based scaling or allometric scaling normalized for differences in microsomal turnover, were used to extrapolate human clearance. For three clinical candidates, including the novel AIDS drug raltegravir (MK-0518, Isentress), oral drug exposure was predicted and compared with that observed in healthy human volunteers. Both scaling methods gave a reasonable correspondence between predicted and ...Continue Reading

References

Jul 1, 1993·Pharmaceutical Research·B Davies, T Morris
May 1, 1996·Biopharmaceutics & Drug Disposition·T IwatsuboY Sugiyama
Mar 22, 2002·The Journal of Pharmacology and Experimental Therapeutics·M G SoarsR J Riley
Oct 9, 2002·Current Drug Metabolism·Jiunn H Lin, Bradley K Wong
Sep 3, 2003·European Journal of Biochemistry·Annalise Di MarcoRalph Laufer
Jun 4, 2004·Journal of Pharmaceutical Sciences·Toshihiro WajimaTakayoshi Oguma
Mar 4, 2005·Journal of Medicinal Chemistry·Erik De Clercq
May 28, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong Tang, Michael Mayersohn
Jun 4, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert J RileyR P Austin
Sep 2, 2005·Journal of Pharmaceutical Sciences·Neil ParrottThierry Lavé
Jan 6, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·C GiulianoR Laufer
Apr 28, 2006·Clinical Pharmacokinetics·Hannah M JonesThierry Lavé
Nov 17, 2006·Bioorganic & Medicinal Chemistry Letters·Alessia PetrocchiVincenzo Summa
Apr 13, 2007·Journal of Medicinal Chemistry·Paola PaceVincenzo Summa
Jun 27, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kelem KassahunLarissa A Wenning
Jul 11, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stefan S De BuckRon A H J Gilissen
Jul 25, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong TangEric Fluhler
Aug 24, 2007·Clinical Pharmacology and Therapeutics·M IwamotoJ A Wagner
Sep 1, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong Tang, Michael Mayersohn
Sep 27, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·E MonteagudoV Summa
Jan 5, 2008·Drugs of Today·Teresa Hope Evering, Martin Markowitz
Jan 26, 2008·Journal of Medicinal Chemistry·Ester MuragliaVincenzo Summa

❮ Previous
Next ❯

Citations

Jul 10, 2013·European Journal of Medicinal Chemistry·N C DesaiAmit Trivedi
Apr 18, 2012·Chemical Research in Toxicology·Xiaohai Li, Michael D Cameron
Mar 22, 2013·The Journal of Antimicrobial Chemotherapy·Darren M MossAndrew Owen
May 5, 2010·Antimicrobial Agents and Chemotherapy·José MoltóBonaventura Clotet
Aug 15, 2014·The Journal of Pharmacy and Pharmacology·Ikuo YamamiyaKen-ichiro Yoshida
Jul 18, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vasu Nair, Maurice Okello
Feb 12, 2014·Expert Opinion on Drug Metabolism & Toxicology·Lizette GroblerHendrik Stefanus Steyn
Sep 10, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Mahamad Yunnus A MahatShilpee Chaudhary
Oct 30, 2016·Drug Testing and Analysis·Swati JaiswalJawahar Lal
Mar 29, 2014·BMC Bioinformatics·Koen Van der BorghtHerman van Vlijmen
Feb 26, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stephanie N LiuBrandon T Gufford
Mar 8, 2017·Chemical Biology & Drug Design·Yasodakrishna SajjaJagadeesh Babu Nanubolu
Oct 31, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Takao Komasaka, Jennifer Dressman

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.