Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
Several software tools are available that facilitate the use of the NONMEM software and extend its functionality. This tutorial shows how three commonly used and freely available tools, Pirana, PsN, and Xpose, form a tightly integrated workbench for modeling and simulation with NONMEM. During the tutorial, we provide some guidance on what diagnostics we consider most useful in pharmacokinetic model development and how to construct them using these tools.
Background
Intravenous-busulfan (IV-busulfan) combined with therapeutic drug
monitoring to guide dosing improves outcomes after allogeneic hematopoietic
cell transplantation (allo-HCT). The best method to estimate busulfan
exposure and the optimal exposure in children/young adults remains unclear.
We therefore evaluated three approaches to estimate IV-Bu exposure
(expressed as cumulative-area-under-the-curve; AUC) and associated
busulfan-AUC with clinical outcomes in children/young adults undergoing
allo-HCT.
Methods
In this retrospective analysis, patients (0.1–30.4 years)
receiving busulfan-based conditioning regimen from 15 centers were included.
Cumulative AUC was calculated by numerical integration using non-linear
mixed effect modeling (AUCNONMEM), non-compartmental analysis
(AUC0-infinity and AUC to the end of the dose interval
AUC0-tau) and by individual centers using a variety of
approaches (AUCcenter). Main outcome of interest was event-free
survival (EFS). Other outcomes of interest were overall survival,
graft-failure, relapse, transplantation related mortality (TRM), acute
toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host
disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival
(GEFS). Propensity score adjusted cox proportional hazard models, Weibull
models, and Fine-Gray competing risk regressions were used.
Results
674 patients were included (41% malignant, 59%
non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan
AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6
mg*h/L). The median AUCNONMEM correlated poorly with
AUCcenter (R2 = 0.254). Patients with optimal
IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years
compared to 66.1% and 49.5% in the low (<78 mg*h/L)
and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011).
Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75
P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in
the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication.
Interpretation
These results demonstrate that improved clinical outcomes may be
achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new
validated pharmacokinetic-model for all indications.
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