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Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes.

Urien S, Bardin C, Bader-Meunier B, Mouy R, Compeyrot-Lacassagne S, Foissac F, Florkin B, Wouters C, Neven B, Treluyer JM, Quartier P - BMC Pharmacol Toxicol (2013)

Bottom Line: Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities.There was no significant effect of the combined anti-inflammatory treatment.The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes.

Methods: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix.

Results: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days.

Conclusions: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.

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Effect of anakinra on the C-reactive concentration-time courses during the ANAJIS trial. The top and bottom plots stand for the 2 response groups : top, responders; bottom, patients with a delayed “resistance” to treatment. Solid and dashed lines, median and 5th/95th percentiles of the final model predictions.
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Figure 2: Effect of anakinra on the C-reactive concentration-time courses during the ANAJIS trial. The top and bottom plots stand for the 2 response groups : top, responders; bottom, patients with a delayed “resistance” to treatment. Solid and dashed lines, median and 5th/95th percentiles of the final model predictions.

Mentions: An indirect response model assuming that the production rate of the inflammatory process is inhibited by anakinra concentrations described well the CRP time-courses in the 22 ANAJIS trial patients (195 observations were available). The C50 parameter was related to the mean steady-state anakinra concentration (Css), allowing the determination of the corresponding dosage to obtain for example 90% of the maximal effect (C90 ~ 10 x C50), i.e., dose rate (mg/h) = CL/F*C90. A mixture model with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a slow re-increase in baseline levels (delayed “resistance” to treatment), was finally retained. The corresponding observed baselines (median [range]), 120 [44, 230] and 43 [2.5, 152] mg/L, were significantly different (p = 0.02, Kruskal-Wallis test). However it was impossible to estimate a clear cut-off value between the 2 groups, probably because of the small sample size. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a “resistance” to treatment was significant was 62% and the corresponding time was approximately 60 days. Table 2 summarizes the results and Figure 2 depicts the CRP observed time-courses and the median and 5th/95th percentiles of the model predictions.


Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes.

Urien S, Bardin C, Bader-Meunier B, Mouy R, Compeyrot-Lacassagne S, Foissac F, Florkin B, Wouters C, Neven B, Treluyer JM, Quartier P - BMC Pharmacol Toxicol (2013)

Effect of anakinra on the C-reactive concentration-time courses during the ANAJIS trial. The top and bottom plots stand for the 2 response groups : top, responders; bottom, patients with a delayed “resistance” to treatment. Solid and dashed lines, median and 5th/95th percentiles of the final model predictions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750485&req=5

Figure 2: Effect of anakinra on the C-reactive concentration-time courses during the ANAJIS trial. The top and bottom plots stand for the 2 response groups : top, responders; bottom, patients with a delayed “resistance” to treatment. Solid and dashed lines, median and 5th/95th percentiles of the final model predictions.
Mentions: An indirect response model assuming that the production rate of the inflammatory process is inhibited by anakinra concentrations described well the CRP time-courses in the 22 ANAJIS trial patients (195 observations were available). The C50 parameter was related to the mean steady-state anakinra concentration (Css), allowing the determination of the corresponding dosage to obtain for example 90% of the maximal effect (C90 ~ 10 x C50), i.e., dose rate (mg/h) = CL/F*C90. A mixture model with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a slow re-increase in baseline levels (delayed “resistance” to treatment), was finally retained. The corresponding observed baselines (median [range]), 120 [44, 230] and 43 [2.5, 152] mg/L, were significantly different (p = 0.02, Kruskal-Wallis test). However it was impossible to estimate a clear cut-off value between the 2 groups, probably because of the small sample size. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a “resistance” to treatment was significant was 62% and the corresponding time was approximately 60 days. Table 2 summarizes the results and Figure 2 depicts the CRP observed time-courses and the median and 5th/95th percentiles of the model predictions.

Bottom Line: Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities.There was no significant effect of the combined anti-inflammatory treatment.The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes.

Methods: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix.

Results: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days.

Conclusions: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.

Show MeSH
Related in: MedlinePlus