Background: The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. Aim: To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. Methods: Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation.Results: Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated.Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. Conclusion:The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles. K E Y W O R D Sfactor IX, factor VIII, population pharmacokinetics | 385 HAJDUCEK Et Al.

BackgroundRecurrence of colorectal cancer (CRC) may arise due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to chemotherapy. Proteins responsible for this recurrence include the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12.MethodsWe evaluated the expression and function of CXCR4 and CD26 in colon cancer cell lines and xenografts following treatment with common chemotherapies using radioligand binding, flow cytometry, immunofluorescence, and enzymatic assays.Results5-Fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry indicated that the decline in CXCR4 was associated with a significant loss of CXCR4+/CD26- cells. Elevations in CD26 were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets revealed drug-dependent responses of CD26/CD44/CD133 populations, suggesting that the benefits of combining standard chemotherapies 5-fluoruracil and oxaliplatin may be derived from their complementary elimination of cell populations.ConclusionOur results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of chemokine gradients through elevation of CD26 activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1702-2) contains supplementary material, which is available to authorized users.

We consider the analysis of spell durations observed in event history studies where members of the study panel are seen intermittently. Challenges for analysis arise because losses to followup are frequently related to previous event history, and spells typically overlap more than one observation period. We provide methods of estimation based on inverse probability of censoring weighting for parametric and semiparametric Cox regression models. Selection of panel members through a complex survey design is also addressed, and the methods are illustrated in an analysis of jobless spell durations based on data from the Statistics Canada Survey of Labour and Income Dynamics. The Canadian Journal of Statistics 40: 1–21; 2012 © 2012 Statistical Society of Canada

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Background Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic treatment. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project generates individually predicted pharmacokinetic profiles relying on concentrate-specific popPK models used for Bayesian forecasting. Objective Specification of a popPK model for the plasma-derived factor VIII (FVIII) concentrate Koate-DVI and its suitability for pharmacokinetic estimation in low-dose scenarios. Methods A popPK model was developed for Koate-DVI WAPPS-Hemo PK data in combination with the existing WAPPS-Hemo Fanhdi/Alphanate model derivation dataset using nonlinear mixed effects modelling, and was validated via cross-validation and prediction-corrected Visual Predictive Checks (pcVPC). Bootstrap and PK outcomes between the Fanhdi/Alphanate and the Fanhdi/Alphanate/Koate models were compared, and the relative error distributions from a limited sampling analysis (LSA) under the latter model for low and normal doses (10 vs 50 IU/kg) and inclusion/exclusion of pre-dose measurements. Results A Fanhdi/Alphanate/Koate model was derived (126 patients, ages 1–71 years) after deeming a Koate-brand covariate not clinically significant, resulting in similar parameter estimates than the Fanhdi/Alphanate model with satisfactory goodness of fit, cross-validation and pcVPC results. Low-dose predictions resulted in a higher accuracy and slightly lower precision of half-life ([Formula: see text]-phase) and time to 2% trough (TAT2%) estimates than normal dose (median absolute bias for half-life: 0.12 vs 0.5%; median interquartile range, IQR: 11.79% vs 9.95%). Precision improved under pre-dose designs by 2 to 3% and remained similar between 5- and 2-sample designs (IQR reduction<1.8%). Conclusions The Fanhdi/Alphanate/Koate model is appropriate for Bayesian forecasting in the WAPPS-Hemo platform, providing a comparable prediction capability for low and normal dosing regimens (10 vs 50 IU/Kg).

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Conventional chemotherapy eliminates the bulk of colorectal cancer (CRC) following surgery. However, recurrence may occur due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to the chemotherapeutic agents. The residual effects of chemotherapy on such surviving cancer cells, and the possible implication for subsequent evolution of metastatic disease, are not well understood. We evaluated the expression and function of the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12. The major CRC chemotherapeutics 5-fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, doxorubicin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on surviving viable cells from HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry revealed that the decline in CXCR4 was associated with a significant loss of CXCR4+ cells. Elevations in CD26 were observed across the entire cell population and were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. CD26-annexin V-propidium iodide co-staining confirmed that CD26 was elevated only on live cells. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets showed that drug treatment and elevated CD26 was most closely associated with enrichment of the CD44+CD133- cell population, suggesting benefits of standard chemotherapy may be derived from selective elimination of cell populations by the combination of complementary drugs 5-fluorouracil and oxaliplatin. Our results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of chemokine gradients through elevation of CD26 activity. Citation Format: Murray J. Cutler, Erica L. Lowthers, Cynthia L. Richard, Dagmar M. Hajducek, Paul A. Spagnuolo, Jonathan Blay. Chemotherapeutic agents attenuate subsequent CXCL12-induced migration of colon cancer cells by selecting for CXCR4-negative cells and increasing peptidase CD26. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B06.