Measurement of Serum Trough Levels of IgG as an Adequate and Beneficial Indicator for Assessing the Pharmacokinetics of Subcutaneously Administered Products
For many patients with primary immunodeficiency, lifelong immunoglobulin substitution is essential to reduce the frequency of severe infections. Subcutaneous home administration is better accepted by patients. However, dosing needs to be customized to the patient. The study presented below may help make therapy individualization easier for doctors and more tolerable for patients.
Introduction
Human immunoglobulin is used for replacement therapy in children and adults, for example in primary immunodeficiency syndrome (PID) with impaired antibody production. In immunoglobulin G (IgG) replacement therapy, individual dose determination based on pharmacokinetics (PK) and the clinical response in a specific patient is crucial to achieve a trough level of IgG (measured before the next dose) within the reference range of serum IgG levels for that age.
Methods of IgG Administration
Human immunoglobulin is available in intravenous and subcutaneous forms. While intravenous administration (IVIG) requires application every 3–4 weeks, the subcutaneous form (SCIG) allows for a more varied dosing regimen (daily to once every 2 weeks). The less invasive SCIG is also associated with a lower risk of systemic side effects. Benefits from SCIG have led to the development of several medicinal products with varying IgG concentrations.
Pharmacokinetic Profile
The PK of IgG differs according to the method of administration. SCIG is associated with slower absorption, leading to a gradual and consistent increase in serum IgG concentration over several days and subsequently achieving a lower maximum concentration (cmax) than IVIG. More frequent SCIG administration compared to IVIG can contribute to more stable IgG levels and less fluctuation between maximum and trough IgG levels.
In clinical practice and clinical trials, the PK profile is most often determined by a series of serum IgG concentration measurements after product administration. The presented study attempted to determine whether using just one measurement, specifically the trough IgG concentration measurement, would be sufficient in estimating PK.
Pharmacokinetic Analysis
The retrospective analysis was based on serum IgG concentration values from participants in two phase II/III clinical trials. Participants included patients older than 2 years with a confirmed diagnosis of PID, who had been on IgG replacement therapy for more than 3 months, and with a serum trough IgG concentration > 5 g/l at screening. In both studies, patients were initially treated with 10% IVIG and later transitioned to 20% SCIG.
Based on actual trough IgG concentrations in participants treated with SCIG once weekly, researchers used computational methods to estimate the area under the serum IgG concentration-time curve (AUCtp). The actual AUC was calculated from repeated serum IgG concentration measurements in study participants. These two AUCs were compared and found to be essentially equivalent. This means that estimating the PK profile of SCIG from the trough concentration is similarly reliable as the PK profile created from repeated measurements.
Since data on 10% IVIG was also available, researchers were interested in whether the PK profile could be similarly estimated from the trough level for IVIG products. However, it was found that the AUC estimated from the trough concentration was about 20% lower than the AUC calculated from repeated serum IgG concentration measurements. Therefore, this estimation method is probably not suitable for IVIG administration.
Discussion and Conclusion
In conclusion, steady-state serum IgG levels remain stable after weekly SCIG treatment in patients with PID and allow for a reliable prediction of total exposure (AUCτ) using serum trough IgG levels. These findings appear to be generalizable across all conventional SCIG medicinal products. The results show that measuring steady-state serum trough IgG levels is a reasonable and beneficial alternative to serial PK sampling during and after clinical development for weekly SCIG treatment PK assessments. For patients and researchers, using steady-state IgG trough levels for PK assessment offers several benefits, including more efficient clinical studies by reducing research costs and logistical demands. More importantly, this approach reduces the burden on patients by decreasing the frequency of blood draws. (lexi)
Sources:
1. Li Z., McCoy B., Engl W., Yel L. Steady-state serum IgG trough levels are adequate for pharmacokinetic assessment in patients with immunodeficiencies receiving subcutaneous immune globulin. J Clin Immunol 2021 Aug; 41 (6): 1331–1338, doi: 10.1007/s10875-021-00990-z.
2. SPC Cuvitru. Available at: www.sukl.cz/modules/medication/detail.php?code=0126808&tab=texts
3. SPC Kiovig. Available at: https://www.ema.europa.eu/en/documents/product-information/kiovig-epar-product-information_cs.pdf
4. SPC Hyqvia. Available at: https://www.ema.europa.eu/en/documents/product-information/hyqvia-epar-product-information_cs.pdf
5. SPC Gamunex. Available at: https://www.sukl.cz/modules/medication/detail.php?code=0207537&tab=text
6. SPC Hizentra. Available at: https://www.ema.europa.eu/en/documents/product-information/hizentra-epar-product-information_cs.pdf
Abbreviated information about HyQvia HERE.
Abbreviated information about Cuvitru HERE.
Abbreviated information about Kiovig HERE.
VV-MEDMAT-84887; preparation date 03/2023
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.
