Multiple amniotic fluid samples

Title: Paul R Has anyone suggestions on how best to code for data that presents maternal plasma and multiple amniotic fluid concentrations? In addition to multiple other data points of plasma from various doses and routes for this tox study, I have simultaneous concentration data from 3 mouse dams (plasma) and samples from the amniotic fluid of three of each of their embryos. Modeling each embryo as another compartment, especially with only the one concentration, is cumbersome and obviously doesn't converge. Should the different embryonic AF concentrations be modeled as 'repeated' samples at this same time point of a specific (AF) compartment, and the differences between them modeling as interoccassion or as an intrasubject variability (ERR)? The latter approach is the one I have taken, but I seek other suggestions as well. Thank you in advance! -- Paul R. Hutson, Pharm.D. Associate Professor UW School of Pharmacy 777 Highland Avenue Madison WI 53705-2222 Tel 608.263.2496 Fax 608.265.5421 Pager 608.265.7000, p7856

Paul, Whatever you do, I would make sure that these extra compartments have no effect on the central compartment. I would first model the plasma concentrations. If you see the difference, you can add categorical covariate ("pregnant") to better describe your subset of interest. Then fix the model parameters and use individual predictions of plasma concentrations as a driving force for the amniotic fluid concentrations (like a two-stage PK-PD model). After you build these separate models (plasma, and then the rest) you can try to re-fit them jointly. If you have just one observation per embryon, it is unlikely that you can distinguish between intra and inter subject variability, so I would put everything to noise (sigma). Leonid -------------------------------------- Leonid Gibiansky, Ph.D. President, QuantPharm LLC web: www.quantpharm.com e-mail: LGibiansky at quantpharm.com tel: (301) 767 5566 Paul Hutson wrote: > Has anyone suggestions on how best to code for data that presents maternal plasma and multiple amniotic fluid concentrations? In addition to multiple other data points of plasma from various doses and routes for this tox study, I have simultaneous concentration data from 3 mouse dams (plasma) and samples from the amniotic fluid of three of each of their embryos. > > Modeling each embryo as another compartment, especially with only the one concentration, is cumbersome and obviously doesn't converge. Should the different embryonic AF concentrations be modeled as 'repeated' samples at this same time point of a specific (AF) compartment, and the differences between them modeling as interoccassion or as an intrasubject variability (ERR)? The latter approach is the one I have taken, but I seek other suggestions as well. > > Thank you in advance! > > -- > > Paul R. Hutson, Pharm.D. > > Associate Professor > > UW School of Pharmacy > > 777 Highland Avenue > > Madison WI 53705-2222 > > Tel 608.263.2496 > > Fax 608.265.5421 > > Pager 608.265.7000, p7856

Dear Dr. Hutson, The general methodological approach with amniotic fluid PK modeling is to pool the fluid from all the sacs at a given time point and measure the concentration in that pooled fluid. The concentrations in the amniotic fluid are generally modeled as a single compartment with other compartments representing the fetus, the placenta, and maternal plasma. There is some elegant work from Dr. Boudinot's group in this area (see below). If you have measured amniotic concentrations from different sacs at each time point then that variability can be simply assigned to noise (sigma) as indicated by Dr. Gibiansky. For my Ph.D. work we were interested mainly in fetal PD and maternal/fetal PK are summarized in the JPET paper indicated below. Fetal PK can be easily modeled by simultaneously analyzing maternal plasma, fetal plasma, and overall fetal tissue concentrations (Both fetal amount and fetal plasma concentrations are needed to estimate the fetal volume of distribution) Huang CS-H, Boudinot FD and Feldman S. Maternal-fetal pharmacokinetics of zidovudine in rats. Journal of Pharmaceutical Science 1996; 85: 965-970. Samtani MN, Pyszczynski NA, Dubois DC, Almon RR, Jusko WJ. Modeling glucocorticoid-mediated fetal lung maturation: I. Temporal patterns of corticosteroids in rat pregnancy. JPET. 2006 ;317:117-26. Warm regards...MNS