Population PD modelling of circulating biomarkers in patients with melanoma treated with interferon alpha2b
Itziar Irurzun-Arana (1), Eduardo Asín-Prieto (1), Salvador Martín-Algarra (2) and Iñaki F. Trocóniz (1).
(1) Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition; University of Navarra, 31008, Pamplona, Spain; (2) Medical Oncology Service, Clínica Universitaria de Navarra, 31008, Pamplona, Spain.
Objectives: To stablish a semi-mechanistic model describing the time course of several circulating biomarkers (LDH, S-100B, and MIA) in advanced melanoma patients treated with adjuvant high-dose interferon-α2b.
Methods: Data related to different biomarker levels in plasma were obtained from 48 melanoma patients (stage IIB/IIC, IIIB/IIIC and IV according to the criteria of the AJCC) treated with adjuvant high-dose interferon-α2b (IFN-α2b) at the University Clinic of Navarra (Pamplona, Spain). The high-dose regimen followed the Kirkwood scheme: 20x106 U/m2/day intravenous in the induction phase (20 doses: 5 days/week during 4 weeks) and 10x106 U/m2/day subcutaneous administration in the maintenance phase (3 days/week during 48 weeks) [2,3]. In total, 17 patients (35%) had at least one dose reduction and 25 patients (52%) had dose delays during the induction or maintenance phase due to toxicity.
LDH, S-100 and MIA concentrations measured in plasma were analyzed simultaneously using the population approach with NONMEM 7.3. Due to the lack of pharmacokinetic data of IFN-α2b, the K-PD approach was used [1].
Results: The structural model developed combines indirect response-based models representing synthesis and degradation processes of tumor biomarkers driven by an underlying latent variable [Tumoral activity (TA)] corresponding to the (unobserved) tumor progression dynamics. Drug effects were incorporated in the model as an irreversible lost (cytotoxic effect) of TA. Two different patterns were seen in the biomarkers profiles: (i) relapse after treatment was stopped, and (ii) disease control over the full period of evaluation. The latter described assuming the presence of long-lasting immune response induced by IFN-α2b.
The proliferation rate of TA in the absence of treatment was 2.3x10-3 weeks-1. Maximal response to treatment appeared after 80 weeks of starting the treatment according to a mean signal transduction time value of 18 weeks. The estimate of the first order rate constant of synthesis of long-lasting immune response was 0.006 weeks-1 for the individuals responding to the treatment, resulting negligible otherwise.
Conclusions: A model for the dynamics of circulating biomarkers has been established and evaluated in patients with melanoma during treatment with IFN-α2b, open the possibility to study the prognosis capability of those biomarkers on disease progression of overall survival using parametric survival analysis.
References:
[1] Jacqmin P., Snoeck E., et al. 2007. “Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model.” J Pharmacokinet Pharmacodyn. 34(1):57-85.
[2] Díaz-Lagares, A., Alegre, E., et al. 2011. “Evaluation of Multiple Serum Markers in Advanced Melanoma.” Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine 32 (6): 1155–61.
[3] Espinosa, E., Soriano, V., et al. 2016. “Treatment Patterns of Adjuvant Interferon-α2b for High-Risk Melanoma: A Retrospective Study of the Grupo Español Multidisciplinar de Melanoma - Prima Study.” Melanoma Research 26 (3): 278–83.
