Background And Objectives: Recently a number of antibody-drug conjugate (ADC) pharmacometric models have been reported in the literature, describing one or two ADC-related analytes. The objective of this analysis was to build a population pharmacokinetic (popPK) three-analyte ADC model to describe efficacy and safety of zilovertamab vedotin, an ROR1-targeting ADC conjugated to monomethyl auristatin E (MMAE).
Methods: Data from a phase 1 study of zilovertamab vedotin in subjects with hematologic malignancies was used in a stepwise ADC modeling strategy based on the simplified ADC popPK model proposed by Gibiansky.
Background: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.
View Article and Find Full Text PDFCPT Pharmacometrics Syst Pharmacol
September 2021
Pharmacometric models can enhance clinical decision making, with covariates exposing potential contributions to variability of subpopulation characteristics, for example, demographics or disease status. Intuitive visualization of models with multiple covariates is needed because sparsity of data in visualizations trellised by covariate values can raise concerns about the credibility of the underlying model. V ACHER, introduced here, is a stepwise transformation of data that can be applied to a variety of static (non-ordinary-differential-equation-based) pharmacometric analyses.
View Article and Find Full Text PDFJ Acquir Immune Defic Syndr
December 2020
Background: Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection.
Methods: IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of raltegravir in infants exposed to HIV-1 infection.
Background: Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates.
Setting: P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection.
Methods: P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations.
CPT Pharmacometrics Syst Pharmacol
September 2019
Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often extremely prolonged, with some neonates demonstrating rising profiles after birth despite removal from the source of extrinsic raltegravir. To establish an appropriate dosing regimen, an integrated maternal-neonatal pharmacokinetics model was built to predict raltegravir plasma concentrations in neonates with in utero raltegravir exposure.
View Article and Find Full Text PDFOptimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.
View Article and Find Full Text PDFA concept relating the lipophilicity of chemicals with their genotoxicity on a chromosomal level had been generated by Schultz and Onfelt (Chem Biol Interact 126:97-123, 2000). It was shown that aneuploidy in Chinese hamster V79 cells was elicited by lipophilic chemicals at concentrations related to their hydrophobicity (log P), whereas toxicants with a specific mode of action acted at concentrations consistently lower than predicted based on log P. We have now combined available data sets on aneuploidy/micronucleus formation with procedures used in QSAR modelling, in order to find new molecular descriptors for modelling non-specific chromosomal genotoxicity, and to optimise combinations thereof.
View Article and Find Full Text PDFRecently we constructed recombinant yeast cells that express the human androgen receptor (hAR) and yeast enhanced green fluorescent protein (yEGFP), the latter in response to androgens. When exposed to 17beta-testosterone, the concentration where half-maximal activation is reached (EC50) was 50 nM. Relative androgenic potencies (RAP), defined as the ratio between the EC50 of 17beta-testosterone and the EC50 of the compound, were 1.
View Article and Find Full Text PDFTo help advance drug discovery projects, a new and validated search method is presented by which potential bioisosteric replacements can be retrieved from a database of more than 700,000 structural fragments. The heart of the search method is an optimized topological pharmacophore fingerprint which describes each fragment as a combination of attachment points, hydrogen bond donors and acceptors, hydrophobic centers, conjugated atoms, and non-hydrogen atoms. In the fingerprint the influence of the attachment point is enhanced by giving it extra weight relative to the other descriptors.
View Article and Find Full Text PDFCarbohydr Res
November 2002
The conformational behavior of the synthetic hexa- and heptasaccharide methyl beta-glycosides alpha-D-Manp-(1 --> 6)-[alpha-D-Manp-(1 --> 3)-][beta-D-Xylp-(1 --> 2)-]beta-D-Manp-(1 --> 4)-beta-D-GlcpNAc-(1 --> 4)-beta-D-GlcpNAc-(1 --> OMe and alpha-D-Manp-(1 --> 6)-[alpha-D-Manp-(1 --> 3)-][beta-D-Xylp-(1 --> 2)-]beta-D-Manp-(1 --> 4)-beta-D-GlcpNAc-(1 --> 4)-[alpha-L-Fucp-(1 --> 6)-]beta-D-GlcpNAc-(1 --> OMe, representing the xylosylated and the xylosylated alpha-(1 --> 6)-fucosylated core structures of N-glycans in alpha(D)-hemocyanin of the snail Helix pomatia, respectively, were investigated by 1H NMR spectroscopy in combination with molecular dynamics (MD) simulations in water. 1H and 13C chemical shifts of the oligosaccharides were assigned using 1H-(1)H COSY, TOCSY, and NOESY, and 1H-(13)C HMQC techniques. Experimental 2D 1H cross-peak intensities from one series of NOESY and one series of ROESY experiments of the two oligosaccharides were compared with calculated values derived from MD trajectories using the CROSREL program, yielding information about the conformation of each glycosidic linkage of the methyl glycosides.
View Article and Find Full Text PDFThe first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy.
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