Primary immunodeficiency diseases (PIDs), also referred to as inborn errors of immunity, reflect a group of more than 480 known diverse conditions affecting the immune system, many of which are often lifelong in nature [1], [2]. Impaired immunity predisposes patients with PIDs to a broad range of infections that most commonly affect the respiratory system and intestinal tract [3], [4]. Immunoglobulin G (IgG) replacement therapy is the standard of care for patients with PIDs who have deficiencies in antibody production [5].

IgG may be administered either intravenously (IVIG), subcutaneously (conventional SCIG), or as hyaluronidase-facilitated subcutaneous treatment (fSCIG), in which IgG is delivered sequentially with recombinant human hyaluronidase (rHuPH20). IgG therapies vary in their pharmacokinetic (PK) profile based on the route of administration and dosing regimen, and each treatment has associated benefits and challenges. IVIG is typically administered once every 3–4 weeks [6], [7], [8] and provides IgG that is immediately bioavailable, which slowly equilibrates to the extravascular compartments [9], [10]. In comparison, conventional SCIG is slowly absorbed from subcutaneous space into the bloodstream via the lymphatic system, resulting in more stable steady-state IgG concentrations than IVIG, although the relatively small infusion volume means that more frequent dosing is required [10]. rHuPH20, which is administered prior to IgG as part of fSCIG therapy, acts to depolymerize hyaluronan in the extracellular matrix to transiently increase tissue permeability to IgG, allowing for greater volumes of IgG to be administered than with conventional SCIG therapy [11]. In addition, conventional SCIG and fSCIG therapies provide greater patient convenience through home-based infusion and carry a lower risk of systemic adverse events than IVIG [5], [10].

Typically, newly diagnosed IgG treatment-naive patients with PIDs have been initiated on IVIG owing to its long history of use in immunodeficiencies [12], [13]. Conventional SCIG is becoming a recognized option for such patients using dosing regimens similar to those switching from other immunoglobulin therapies [7], [13], [14]. Similarly, fSCIG may be a viable option when administered at the same dose and frequency as IVIG treatment following a dose ramp-up schedule [15], [16]. While conventional SCIG has been shown to decrease the burden of infection and elevate IgG trough concentrations in both IgG treatment-experienced and -naive patients [13], there is a paucity of literature and clinical studies examining the use of subcutaneous IgG therapies in treatment-naive patients with PIDs.

Where clinical data are sparse, a population pharmacokinetic (popPK) modeling approach can be applied to investigate PK variability across various treatment regimens and patient factors, with a view to informing dose optimization for clinical use [17], [18]. Using a single-compartment popPK model, a prior study simulating conventional SCIG loading and maintenance doses in IgG treatment-naive patients with PIDs showed that protective IgG concentrations can be achieved in this population in a timely manner [19]. An integrated popPK model has previously been developed using data from patients with PIDs treated with a range of IVIG, conventional SCIG, and fSCIG therapies and dosing regimens [20]. The model incorporated endogenous production of IgG and a unique separate bioavailability of subcutaneous therapies with and without rHuPH20. This model robustly described IgG PK profiles, providing a framework for investigation of IgG PKs for a variety of IgG therapies and dosing regimens, and in populations of special interest such as IgG treatment-naive patients with PIDs [20].

The objective of this study was to use model-based simulations to characterize IgG PKs in treatment-naive patients with PIDs with varying disease severity, following administration of different IVIG, conventional SCIG, or fSCIG doses and dosing regimens, using an integrated popPK model.