Modeling of Red Blood Cell (RBC) Lifespan (LS) in a Hematologically Normal Population
Robert M. Kalicki, Rocío Lledó-García, Mats O. Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Recently, Cohen et al[1] published an original work focusing on the effect of RBC LS heterogenicity on formation of glycosylated hemoglobin (HbA1c). An individual approach using a cubic fit was performed to describe the decay of biotin-labelled RBC over time. The aim of this work was to reanalyse the data using a more physiological model, based on a finite RBC LS and random destruction rate (RDR)[2], and taking into account the IIV as a basis for the development of future models which will be applied in the HbA1c modelling area.
Methods: Biotin-labelled RBC survival-Time profiles from 6 diabetic and 6 non-diabetic subjects1 were first digitalized using two different softwares (TechDig and xyExtract Graph Digitalizer). For each time record the average of both digitalized values was taken providing a satisfactory precision (mean SD of 0.4% units). Different models taking into account the finite RBC LS with or without a random destruction rate were fitted to the data using NONMEM VI: (i)zero-order decay; (ii)combined zero-first order decay; (iii)transit compartment model; (iv)transit compartment model with RDR. The RDR-Time profile was further investigated. Both estimates of LS and RDR, as well as the optimal number of transit compartments (NCOMP), were evaluated. The slope-intercept residual error was used.
Results: Overall, transit compartment models showed a better performance compared to zero and zero-first order decay models. The addition of an overtime linearly increasing RDR did considerably further improve the fit. The mapping of the NCOMP and OFVs values permitted to determine the optimal NCOMP for the simple transit compartment model (NCOMP=12, OFV=345.6, LS=91.8 d). Whereas for the extended model with RDR, the optimal NCOMP could not be established because of an intrinsic NONMEM limitation in the NCOMP (NCOMP=29, OFV=272.3, LS=103, RDR=0.209%/d). However, the mapping of the OFV showed an asymptotic profile with insignificant gain when increasing the NCOMP. No significant difference of estimated parameters could be found between diabetic and non-diabetic subjects.
Conclusions: Our preliminary work confirms the presence of both mechanisms (lifespan and RDR) responsible for the natural elimination of RBC. The implementation of the transit compartment model using the maximum allowed number of compartments with RDR linearly increasing over time showed to be superior and needs to be considered in future.
References:
[1] Cohen RM, Franco RS, Khera PK et al. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008; 112(10): 4284-4291.
[2] Berlin N.I., Waldmann T.A., Weissman S.M. Lifespan of Red Blood Cell. Vol. 39. Metabolism Service, General Medicine Branch, National Cancer Institute, Bethesda, Maryland.
