Immunoglobulin therapies for primary immunodeficiency diseases (part 2): considerations for dosing strategies

Abstract

Immunoglobulin G (IgG) dosing in treating primary immunodeficiency diseases (PIDs) is individualized, which often involves regular monitoring of IgG levels, and considers patient experiences with immunoglobulin therapies, their clinical status and physician judgment. The frequency and dose(s) of intravenously (IVIG) and subcutaneously (SCIG) administered IgGs (including hyaluronidase-facilitated SCIG) require rigorous evaluation to maximize therapeutic benefits. Monitoring serum IgG levels represents an integral part of diagnosing primary immunodeficiency diseases and determining or adjusting IgG dosing strategies to meet individual patient needs, but cannot be conducted in isolation. This review discusses the current state and future perspectives on dosing strategies for different types of IgG therapies, as well as dosing considerations for specific patient populations, immunoglobulin-naive patients and patients switching between IVIG and SCIG.

Plain Language Summary

Primary immunodeficiency diseases (PIDs) are a group of genetic conditions where the immune system does not work properly. Antibodies produced by the immune system help the body fight infections. PIDs can be treated with a type of antibody called immunoglobulin G (IgG), which can be given into the vein or under the skin. Determining what dose of IgG should be given to a person involves blood tests, doctors’ judgment and preferences of people for how they receive treatment. Here we discuss the current strategies for choosing the right dose of IgG as well as future perspectives. We also reflect on how these methods may vary for different groups of people with PIDs, and for people starting or switching between treatments.

Tweetable Abstract

Part 2 of our two-part series on IgGs for primary immunodeficiency diseases reviews dosing strategies and considerations for specific populations receiving various IgG therapies. #IVIG #SCIG #immunotherapy

Plain language summary

Article highlights.

Dosing of SCIG

• The dosing strategy for immunoglobulin G (IgG) for treating primary immunodeficiency diseases (PIDs) requires individualization based on serum IgG trough levels, clinical response and the patient’s past experiences with Ig therapies.

• Substantial variability in the pharmacokinetics (PK) and clinical response to IgG therapy have led to the proposal of individualized therapy for maximizing therapeutic benefit.

IgG dosing guided by target IgG trough levels

• While IgG trough has been widely used as a surrogate marker for guiding dose adjustment, there are still gaps in understanding the relationship between dose, IgG levels/exposure and clinical outcomes.

• Monitoring serum IgG levels has been an integral part of diagnosing PIDs and determining or adjusting IgG dosing scheme in patient care to meet individual needs, but monitoring cannot be used in isolation. The frequency and dose(s) of intravenous immunoglobulin and subcutaneous immunoglobulin (SCIG; including hyaluronidase-facilitated SCIG) require rigorous evaluation to provide optimum therapeutic benefit to patients with PIDs. Dosing strategies vary among different products and between dosing routes.

Dosing strategies in specific populations and immunoglobulin-naive patients

• Body weight-based dosing for Ig therapies remains valid for all patients, including pediatric or obese patients. There has not been compelling evidence to justify a different dosing approach.

• The use of SCIG treatment, irrespective of patients receiving prior intravenous immunoglobulin or being treatment naive, may lead to similar outcomes. Model-based simulations indicate the need for loading doses to attain a protective IgG threshold in Ig-naive patients with PIDs when initiating SCIG. However, further clinical studies are needed to generate robust evidence for using SCIG in Ig-naive patients with PIDs.

1. Introduction

Immunoglobulins have been used for the treatment of immune deficiencies ever since Bruton administered an immunoglobulin to a child with agammaglobulinemia in the 1950s [1]. Over the years, more than a dozen immunoglobulin G (IgG) therapies have been developed and approved for the treatment of primary immunodeficiency diseases (PIDs; alternatively referred to as inborn errors of immunity [2]).

Due to proteolytic degradation in the stomach and intestine, immunoglobulins are typically administered parenterally via the intravenous (IVIG) or subcutaneous (SCIG) route. Both have their advantages and disadvantages (Table 1) [3–10], but provide an equal magnitude of clinical benefit [3]. Several dosing strategies have been proposed to treat patients with immunodeficiencies. However, gaps in understanding remain with respect to optimizing IgG dosing in an individual patient or a patient population.

Table 1.

A comparison of dosing strategies and pharmacokinetics between intravenous immunoglobulin, subcutaneous immunoglobulin administration.

Comparison parameters	IVIG 10%	SCIG 20%	fSCIG 10%
Infusion frequency	Every 3–4 weeks	Daily to every 2 weeks (pump administration) Daily to every 3 to 4 days (manual administration)a	Every 2–4 weeks
Infusion volumeb	Large (700 ml)	Small (5–10 ml for daily infusion). Smaller volume allows gradual absorption and achievement of steady-state levels	Large (280–560 ml every 4 weeks)
Infusion time	3–5 h/dose every 3–4 weeks	∼1 h/dose every 1–2 weeks (pump administration) 5–10 minutes/dose every 1–2 days (manual administration)a	3–5 h/dose every 3–4 weeks
Use of high doses	Possible	Limited by volume and number of sites	Possible
Infusion route	IV, requires venous access	SC, no requirement for venous access	SC, no requirement for venous access
Pharmacokinetics	Rapid rise in IgG levels and then gradual decline, ultimately reaching baseline levels	Slower increase in IgG levels compared with IVIG, but decline in levels is slow with subsequent stable levels	Faster increase in IgG levels compared with SCIG
	High peak/trough fluctuation	Low peak/trough fluctuation or higher trough than IVIG and fSCIG	Intermediate trough level, dependent on treatment interval
	100% bioavailability	Generally 60–70% bioavailabilityc	>90% bioavailabilityc
Local adverse events	Rare	Frequent, but mild to moderate	Similar to SCIG; mild and common and diminish with continued use
Systemic adverse events	Frequent	Rare	Similar to SCIG; milder than for IVIG
Administration	Skilled personnel needed	Self-administration is possible	Self-administration is possible
Level of patient satisfaction	Preferred by patients who do not want frequent dosing	Preferred by patients who want independence and who are willing to self-administer	Preferred by patients who have poor venous access or when frequent SCIG infusions are problematic
Cost	High	Low	Low

^aManual administration is by hand using a conventional syringe and butterfly needle and offers quicker administration times compared with an infusion pump due to lower infusion volumes [11].

^bIn these examples, indicative infusion volume is based on an individual weighing 70 kg and is dependent on the formulation of the medication.

^cBioavailability relative to IVIG.

fSCIG: Hyaluronidase-facilitated subcutaneous immunoglobulin; IgG: Immunoglobulin G; IVIG: Intravenous immunoglobulin; SCIG: Subcutaneous immunoglobulin.

The American Academy of Allergy, Asthma and Immunology has provided guiding principles for the appropriate use of IVIG in patients with PIDs [4]. These general principles can also largely be applied to SCIG use and are summarized below.

• Indication: IVIG is indicated as replacement therapy for PIDs characterized by absent or deficient antibody production. This is a US FDA-approved indication for IVIG, for which all currently available products are licensed.

• Diagnoses: there are many PID diagnoses for which IVIG is indicated and recommended. Many are characterized by minimal-to-low total IgG levels in circulation, but some have a normal level with documented specific antibody deficiency.

• Frequency of treatment: IVIG is indicated as continuous replacement therapy for PIDs. Treatment should not be interrupted once a definitive diagnosis has been established.

• Dose: IVIG is indicated for patients with PIDs at a starting dose of 400–600 mg/kg every 3–4 weeks. Less frequent treatment, or use of lower doses, is not substantiated by clinical data.

• IgG trough levels: although IgG trough levels can be useful in some diagnoses of PIDs for guiding dosing strategies in patient care, they are not useful in many other PID diagnoses and should not be a consideration in access to IVIG therapy.

• Site of care: the decision to infuse IVIG in a hospital, hospital outpatient, community office or home-based setting must be based upon the clinical characteristics of the patient.

• Route: route of administration must be based on patient characteristics. Most patients with PIDs are appropriate candidates for IVIG and a subset for SCIG therapy.

• Product: IVIG or SCIG are not generic drug products and various approved Ig products are not interchangeable. A specific product needs to be matched to patient characteristics to ensure patient safety and tolerability. A change of product should occur only with the active participation of the prescribing physician. While the common active component of Ig products is IgG, IgG concentrations and formulations can vary significantly, and physicians should consider all product-related factors and patient characteristics when matching a product to a patient [12–16].

It is widely believed that to provide therapeutic benefit of IgG therapies to patients with PIDs, one needs to achieve a minimum IgG concentration. An IgG trough level of 5 g/l is considered to be generally sufficient to provide therapeutic benefits and protection against infections [17]. However, in recent years, clinical monitoring of patients with PIDs has shown that IgG trough levels of 7–10 g/l are more effective in the prevention of infections, particularly pneumonia [17–23], and thus targeting this higher threshold should be considered in patients with comorbidities such as chronic lung diseases [16,19]. As the protective threshold varies between individual patients, treatment should be individualized to allow for appropriate dosing and infusion intervals to achieve optimal IgG trough levels [21].

2. Dosing of SCIG

The subcutaneous route of administration is well recognized as offering ease of administration and convenience to both patients and healthcare professionals, and has become more popular in recent years [24–26]. There are situations, particularly in the adult population, where conventional SCIG may be preferred over IVIG, including patients at thrombotic risk, those with poor or difficult venous access (e.g., infants and small children), adults with compromised venous access or a need to preserve access (e.g., patients receiving chemotherapy) and those with previous history of systemic reactions to IVIG [5,24]. There are two categories of SCIG products, conventional SCIGs and recombinant human hyaluronidase (rHuPH20)-facilitated SCIGs (fSCIGs). SCIG therapies have not been indicated for use in patients with PIDs.

Patients typically initiate an SCIG product by switching from another IVIG or SCIG product. For those switching from IVIG, treatment is initiated 1 week after the last IVIG dose and dosing frequency ranges from daily to every 2 weeks [3]. The weekly dose, according to FDA labels, is established by converting the monthly IVIG dose into equivalent weekly dose and increasing using a dose adjustment factor (1.3–1.5) [26,27]. Frequent dosing (2–7 times per week) is achieved by dividing the calculated weekly dose by the desired number of times per week; or less frequent dosing, i.e., biweekly dosing, is achieved by multiplying the calculated weekly dose by 2. In the EU, there is no dosing conversion factor for switching between IVIG and SCIG [6,28]. There is limited evidence to clearly support the advantage of one dosing schedule over the other. One prospective, open-label, multicenter, single-arm, Phase III study of 51 patients with PIDs treated with the SCIG 20%, IgPro20 (HIZENTRA; CSL Behring AG, Bern, Switzerland), over 40 weeks, concluded that IgG levels were maintained without dose increases, and patients were effectively protected against infections [29]. However, two extension studies in the EU (low dose, 116.0 mg/kg) and the USA (high dose, 193.2 mg/kg), which assessed the long-term efficacy and tolerability of IgPro20 in patients with PIDs, revealed that rates of any infection were 3.33 per subject/year in the EU and 2.38 per subject/year in the USA [30]. Furthermore, the rate of bronchopulmonary infections was higher in the EU study. Mean steady-state IgG trough levels were higher in the US study. These two studies indicate that higher IgG trough levels may be beneficial to patients with PIDs. Considering that the doses of SCIG were much higher in the US studies than the EU studies, and the clinical benefits in terms of serious bacterial infections were similar in both studies, using a low dose of SCIG is beneficial from a dose consumption and economic perspective. However, additional clinical studies are needed to determine whether bioavailability of SCIG doses needs to be adjusted, as there are advantages from the higher dose in terms of preventing nonbacterial infections, absenteeism from school/work, days spent in hospital and use of antibiotics. However, observations made in these earlier extension studies appear to support the use of higher doses for the treatment of serious bacterial infections [28,31] and that a bioavailability-adjusted dose may be beneficial.

For patients switching between SCIG products, dosing level and interval remain the same [7].

The European Medicines Agency guidelines on core summaries of product characteristics for conventional SCIG recommends the following dosing strategy for patients with PIDs [31]: ‘The dosage regimen should achieve a sustained level of IgG. A loading dose of at least 0.2–0.5 g/kg (200–500 mg/kg) body weight may be required. This may need to be divided over several days, with a maximal daily dose of 0.1–0.15 g/kg. After steady-state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.4–0.8 g/kg (400–800 mg/kg). Trough levels should be measured in order to adjust the dose and dosage interval. The dosage may need to be individualized for each patient dependent on the pharmacokinetics (PK) and clinical response’.

Several caveats associated with conventional SCIG should be noted. Absorption is slow compared with IVIG, with maximum concentration (C_max) generally reached 2–4 days after administration [32]. The extent of absorption may depend on IgG degradation by proteolytic enzymes, like other biologics including monoclonal antibodies [33,34]. Saturation of proteolytic enzymes may lead to increased bioavailability (nonlinear) with increasing doses of IgG. However, large doses (>500 mg/kg) cannot be administered due to the limited solubility of IgG and large-volume limitations for subcutaneous administration [23,25]. Given the differential exposure between IVIG and SCIG, the FDA suggests the use of a conversion factor for adjustment of conventional SCIG dose based on absolute bioavailability (measured against the exposure of IVIG) of a product, and the dose of SCIG is generally 1.3- to 1.5-fold higher than that of IVIG [7,35]. Following conventional SCIG administration, C_max is lower and minimum concentration (C_min) is higher than with IVIG.

The absolute bioavailability of conventional SCIG can be enhanced by using rHuPH20 to facilitate the absorption of SCIG. For example, fSCIG 10% (HYQVIA; Baxalta US, Inc., a Takeda company, Lexington, MA, USA) – approved for the treatment of PIDs in adults and children aged ≥2 years in the USA [27], and in patients of all ages with PIDs in Europe [36] – comprises a dual-vial unit, with one vial containing 10% IgG (100 mg/ml) and the other containing 160 U/ml rHuPH20. rHuPH20 depolymerizes hyaluronan in the extracellular matrix, transiently increasing the permeability of subcutaneous tissue to IgG, thus increasing dispersion and absorption of the IgG, resulting in increased bioavailability [37]. The use of rHuPH20 allows high-volume Ig administration (up to 600 ml/infusion site over 2–3 h) into the subcutaneous tissue over a short time and permits higher infusion rates and reduced dosing frequency compared with conventional SCIG [37].

The area under the concentration-time curve (AUC) of fSCIG 10% compared with conventional SCIG without rHuPH20 is 20% higher, and the weekly AUC-based bioavailability of fSCIG 10% is 93.3% of IVIG [8]. The use of rHuPH20 in combination with IgG has enabled direct 1:1 dose conversion from IVIG to fSCIG 10%, or vice versa, with no adjustment required for bioavailability [27]. For patients switching from fSCIG 10% to conventional SCIG, the dosing strategy is the same as switching from IVIG to conventional SCIG, as discussed above [38].

2.1. Ramp-up dosing for fSCIG 10%

The initiation of fSCIG 10% treatment requires an initial dose ramp-up. For patients naive to SCIG treatment or switching from SCIG, after initial dose ramp-up, an fSCIG 10% dose of 300–600 mg/kg at 3- to 4-week intervals should be administered. For those switching from IVIG, the dose and frequency will stay the same as the previous IVIG treatment after the initial dose ramp-up. The dose ramp-up period is intended to incrementally increase infusion volumes to achieve target dose and allow patients a time period within which to adapt to large-volume subcutaneous infusions (several hundred ml). The following ramp-up schedule is included in the current US prescribing information for fSCIG 10% for the treatment of PIDs: for a 4-week dosing interval, the first dose is initiated at 25% of the target full dose in week 1, increasing to 50% in week 2, 75% in week 4 and 100% in week 7 (Table 2) [25,27]. In the EU summary of product characteristics for fSCIG 10%, at treatment initiation, it is recommended that the treatment intervals for the first infusions be gradually extended from a 1-week dose up to a 3- or 4-week dose [36]. The cumulative monthly dose of IgG 10% should be divided into 1 week, 2 week etc. doses according to the planned treatment intervals with fSCIG 10% [36].

Table 2.

Initial treatment interval/ramp-up dosing schedule for hyaluronidase-facilitated subcutaneous immunoglobulin 10%.

Week	Infusion number	Dose interval	Example for 30 g per 4 weeksa
1	1	1-week dose	7.5 g
2	2	2-week dose	15 g
3	No infusion	N/A	N/A
4	3	3-week dose	22.5 g
5	No infusion	N/A	N/A
6	No infusion	N/A	N/A
7	4 (if required)	4-week dose	30 g

^aIn this example, 1-week-dose is equivalent to one quarter of the monthly dose; 2-week-dose is equivalent to one half of the monthly dose.

fSCIG: Hyaluronidase-facilitated subcutaneous immunoglobulin; N/A: Not applicable.

Recently, ramp-up dosing for fSCIG 10% was evaluated in a Phase I, open-label, randomized, single-center study in healthy adults [39,40]. The aim of the study was to assess the safety and tolerability of modified ramp-up dosing schemes versus the current scheme included in the US prescribing information. In this study, participants were assigned to one of the three ramp-up arms to achieve a target dose of 0.4 g/kg/infusion (low dose) or 1.0 g/kg/infusion (high dose): conventional dose ramp-up (0.1 or 0.25 g/kg [week 1] to 0.4 or 1.0 g/kg [week 8], respectively); abbreviated dose ramp-up (0.2 or 0.5 g/kg [week 1] to 0.4 or 1.0 g/kg [week 5], respectively); or no ramp-up. Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated. Infusion rate was reduced in one participant owing to headache in the low-dose conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm versus the conventional and accelerated ramp-up arms for the high target dose. Safety outcomes did not substantially differ between treatment arms. The favorable tolerability and safety profiles demonstrated in healthy adults were considered to be supportive of initiating treatment with fSCIG 10% with accelerated ramp-up at target doses of up to 1.0 g/kg; additional data for no ramp-up are needed for higher target doses [39,40]. Overall, to help patients initiate or transition to high-volume infusions more comfortably, there is evidence to support the individualization of fSCIG 10% administration schedules according to physician discretion based on patient tolerability.

In summary, the subcutaneous route of administration for IgG replacement therapy has been used increasingly over the past decade. Advantages of conventional SCIG over IVIG include relatively stable steady-state IgG levels, and the convenience of self-administration. In addition, SCIG can offer substantial savings in overall costs compared with IVIG [9,41]. Dosing strategy for SCIG varies depending on the original IgG therapy or route of administration. A dosing conversion factor (switching between IVIG and conventional SCIG) may be required per regional labels, or a dose ramp-up scheme required in the case of initiating fSCIG 10%.

3. IgG dosing guided by target IgG trough levels

The use of serum IgG trough levels in guiding the dosing of patients with PIDs is widespread. However, guiding dosing in PIDs based on IgG trough levels alone has not been proven to be adequate. There is currently no consensus regarding the dose, dosing interval and the maximum and minimum concentrations of IgG and their relationship with therapeutic benefit. Similarly, evidence for a correlation between IgG trough levels and clinical outcomes is mixed.

In a meta-analysis evaluating the relationship between IgG trough levels and pneumonia incidence in patients with PIDs following IVIG treatment (17 studies evaluated; 676 patients and 2127 patient-years of follow-up), pneumonia incidence declined by 27% with each 1 g/l increment in IgG trough [36]. Pneumonia incidence with maintenance of 5 g/l IgG trough levels (0.113 cases per patient-year) was five-fold higher than in patients with 10 g/l trough levels (0.023 cases per patient-year). The authors concluded that there was strong evidence that the risk of pneumonia could be reduced by achieving higher IgG trough levels [42].

Another meta-analysis of 13 studies (482 patients) evaluating eight different SCIGs (mostly administered once or twice a week) attempted to establish a correlation between SCIG dose and minimum IgG trough levels with clinical outcomes in patients with PIDs [37]. The occurrence of serious bacterial infections was rare in all studies, and some reported none. Although no correlation was found between IgG dose, serum IgG concentration and the annual rate of serious bacterial infection, the annualized rate of overall infection correlated inversely with serum IgG levels. When only prospective studies were considered, the correlation was significant (r = -0.682; p = 0.030). This corresponded to a decrease in the annual rate of infection of 0.38 events/patient/year for every 1 g/dl increase in serum IgG concentration [43].

In an evidence-based review of 25 studies in which patients with PIDs were administered IVIG or SCIG, it was revealed that IgG trough levels were higher with SCIG administration than with IVIG administration [44]. However, both routes of administration provided protection from serious bacterial infections and were well tolerated. The authors concluded that it was not possible to determine which route of administration was preferable to the other, at least not from an efficacy and safety perspective.

In a further meta-analysis (24 studies evaluated) assessing IgG trough levels and efficacy of IVIG (13 patients) and SCIG (11 patients) treatment for PIDs, higher mean trough levels were seen with weekly SCIG administration compared with monthly IVIG administration (mean difference, 0.73 g/l) (Figure 1) [23]. For every 1 g/l increase in IgG trough level, a linear trend for decreased incidence of infection was observed in SCIG-treated patients (p = 0.03). Indeed, infection incidence with an IgG trough level of 8–9 g/l was 4.97 events (95% confidence interval [CI]: 4.3–5.8), which decreased to 1.85 events (95% CI: 0.14–3.6) with a trough level of 12 g/l. These trends were not seen with IVIG therapy (p = 0.67). However, in the six studies where incidence of infection was compared between IVIG and SCIG, the difference in risk of overall infections or serious infections was not statistically significant.

Figure 1.

Immunoglobulin G trough levels following treatment with conventional subcutaneous immunoglobulin versus intravenous immunoglobulin.

This figure has been adapted with permission from [23], Elsevier Inc.

CI: Confidence interval; IV: Intravenous; IVIG: Intravenous immunoglobulin; SCIG: Subcutaneous immunoglobulin; SD: Standard deviation.

Finally, results from seven studies of four different SCIG preparations in patients with PIDs showed that there was an inverse linear relationship (r = -0.812; r² = -0.659) between annualized infection (other than acute serious bacterial infections) incidence and steady-state serum IgG concentrations [45]. However, the authors concluded that no given level is necessarily adequate for all patients.

The current state of evidence remains supportive of the fact that serum IgG trough levels are a highly relevant surrogate marker for therapeutic efficacy of IgG in PIDs. Nonetheless, available evidence also highlights the inter-patient variability in the so-called ‘protective threshold’ that drives the ultimate dosing and dosing optimization strategy for individual patients.

4. Dosing strategies in specific populations

The dose of Ig treatment is based on body weight. There may be considerable variation in body composition between individuals, particularly in the context of children and adults, or between patients with a healthy body mass index and patients who are obese. The optimal approach to determining doses of Ig treatment has therefore long been a subject of debate [46]. For all the approved Ig therapies, there is no recommendation for dose adjustment for specific populations.

There has been a long-standing debate around the optimal approach to determining doses for all patients [47–49]. Perhaps one of the most practical questions for Ig replacement therapy in PIDs is still how dosing can be optimized in specific populations such as young children or patients with obesity, to balance treatment benefits and the potential risk of adverse events. These two populations of interest represent those with different body mass composition that may affect how IgG is absorbed, distributed and eliminated. The potential intrinsic and extrinsic patient factors that may result in differences in the PK profiles of IgG have been discussed comprehensively in Part 1 of this review series. Additionally, given the high cost of IgG therapies and increased infusion time, administering higher doses than necessary has implications for healthcare resource utilization and patient burden [25].

Clinical data comparing efficacy of IgG at different dose levels or using different dosing regimens in pediatric or obese patients with PIDs are still lacking. However, there is some evidence indicating that initial loading doses of IVIG (typically 2 g/kg over 2–5 days) should be based on ideal body weight rather than adjusted body weight in patients with PIDs who are obese [50]. Previously published modeling results support the current body weight-based dosing for both populations, despite a trend for decreased IgG exposure in younger patients and increased exposure in patients with PIDs who are obese [45,51].

While it is acknowledged that polymorphisms encoded by the IGHG1, IGHG2 and IGHG3 genes may influence antibody function [52], there is very little evidence in the literature regarding impact of polymorphisms on IgG PK.

5. Dosing strategies in immunoglobulin-naive patients

IVIG has been the standard of care for initiation and long-term treatment of patients with PIDs and enables rapid attainment of target serum IgG levels. Patients newly diagnosed with PIDs who are Ig-naive are frequently initiated on IVIG. Treatment with SCIG is most often initiated in Ig-experienced patients, but can be initiated directly [53–55]. Although it may be generally accepted and common practice in the EU to initiate patients with PIDs on SCIG, data from clinical studies in Ig-naive patients who are initiated on SCIG are limited [53].

In a study of the safety and efficacy of IVIG 16% (Vivaglobin; CSL Behring GmbH, Marburg, Germany) or IgPro20 in older (mean age, 70 years) Ig-naive patients with antibody deficiency syndromes, patients were initially given subcutaneous IgPro20 100 mg/kg twice weekly for 2 weeks followed by a weekly dose of 100 mg/kg [48]. Baseline IgG levels were 4.60 ± 1.46 g/l and increased following SCIG administration. The mean IgG serum levels after SCIG administration at Months 1, 3 and 6 were 8.52 ± 1.06, 9.07 ± 1.57 and 9.43 ± 1.82 g/l, respectively. One patient developed sepsis/cholangitis unrelated to treatment; no other serious bacterial infections were reported. All patients remained on SCIG therapy for a median of 44 months. The authors concluded that the initiation of SCIG by doubling the maintenance dose over 2 weeks may be a well-tolerated and effective option for patients with antibody deficiencies requiring IgG replacement, especially among older patients [56].

PK data are widely available from Ig-experienced patients with PIDs, but rather limited PK data are available from Ig-naive patients. Population PK (popPK) studies may be used to understand dosing in Ig-naive patients with PIDs, and there have been several popPK model-based simulation studies conducted to better understand the PK of IgG in these patients. One popPK study simulated IgG profiles in Ig-naive patients with PIDs receiving different doses of SCIG 20%, Ig20Gly (CUVITRU; Baxalta US Inc., a Takeda company, Lexington, MA, USA) [57]. Endogenous baseline IgG levels were set at 1.5, 2, 4 and 6 g/l, and the therapeutic target (IgG trough level) was set as 7 g/l. When the total loading dose was 400 mg/kg and the maintenance dose was 100 mg/kg weekly, target IgG trough levels were achieved in 1–8 weeks and occurred earlier for patients with higher baseline IgG levels. For patients with baseline levels of 4 or 6 g/l, target IgG trough levels were achieved earlier if the loading dose was divided over several days of a single week instead of over a 2-week period. When the total loading dose was 800 mg/kg and the maintenance dose was 200 mg/kg weekly (and when the loading dose was divided over several days of a single week instead of over a 2-week period), target IgG trough levels were achieved in 1–3 weeks. For patients with baseline IgG levels of 6 g/l, target IgG trough levels were achieved within 1 week. Overall, this simulation study indicated that Ig-naive patients with PIDs can achieve target IgG levels within a few weeks depending on their baseline IgG levels, loading dose and maintenance dose. The lower the baseline IgG levels in patients with PIDs, the higher the loading and maintenance doses required and the longer the time to achieve the target levels [57].

In another popPK study performed to predict IgG concentration-time profiles and exposure metrics, such as steady-state AUC, C_max and C_min of IgPro20 in Ig-naive patients with PIDs, baseline endogenous values were set at 1.5 g/l and 4 g/l [58]. A weekly dosing regimen was compared with more frequent (daily, five times a week, three times a week and twice a week) and less frequent (biweekly, every 3 weeks and every 4 weeks) dosing regimens. The SCIG dose remained unchanged throughout (100 mg/kg/week). Dosing biweekly or more frequently provided overlapping steady-state concentration-time profiles and similar AUC, C_max and C_min values. The minimum IgG exposure was slightly higher (8%) with more frequent dosing. When dosing every 3 or 4 weeks, IgG concentrations had higher peaks and lower troughs, with less than 90% of steady-state levels toward the end of the dosing interval. A similar observation occurred in subjects with lower (1.5 g/l) baseline IgG levels. Without a loading dose, the time to reach the targeted level of 7 g/l was 13 weeks and 24 weeks when the baseline endogenous IgG levels were 4 and 1.5 g/l, respectively. In patients with baseline endogenous IgG level of 4 g/l, the time to reach levels above 7 g/l and 90% steady-state was within 1 week when an IgG dose of 100 or 150 mg/kg was administered five times a week during the first week of treatment. In patients with endogenous IgG level of 1.5 g/l, the time to reach levels above 7 g/l and 90% steady-state was within 1 week when the IgG dose of 150 mg/kg was administered five times a week during the first week of treatment. The 100 mg/kg IgG five times a week dose did not achieve IgG levels above 7 g/l until week 21 [58]. A similar observation was made in a prospective, open-label, multicenter, 6-month study of 18 treatment-naive patients with PIDs receiving SCIG 16% (Vivaglobin) 100 mg/kg for 5 consecutive days (total loading dose 500 mg/kg) [59]. The maintenance dose was 100 mg/kg/week. The primary efficacy endpoint of IgG levels ≥5 g/l on day 12 was achieved in 17 patients. The authors concluded that IgG therapy can be initiated in previously untreated patients with PIDs directly with SCIG.

In a study using popPK model-based simulations to characterize IgG PK in IgG-naive patients with varying disease severity across several IVIG, SCIG and fSCIG dosing regimens, across all therapies, C_min,ss tended to increase with age, dose and endogenous IgG concentration [52]. Although the findings were model-based and not a summarization of real-world observations, it was concluded that equivalent doses ≥800 mg/kg every 4 weeks with corresponding loading regimens may be required to achieve target IgG levels in treatment-naive patients, especially at low endogenous starting concentrations [60].

Although a wealth of evidence is available for patients switching from IVIG to SCIG, less information is available for treatment-naive patients initiating SCIG. A systematic review assessing outcomes and PK in both of these populations has concluded that outcomes in these patients will likely be similar, although additional studies in the IVIG-naive population are needed to confirm this finding [53].

SCIG may become an attractive option for IgG-naive patients. A loading dose preceding the regular maintenance dose may enable rapid attainment of adequate serum IgG levels and more stable IgG trough levels than IVIG after the loading phase.

6. Conclusion

Current dosing strategies for IgG in the treatment of PIDs are individualized and empirical to a certain extent. Widely used dosing strategies include IVIG doses (400–600 mg/kg) given every 3–4 weeks, or for conventional SCIG (when switching to this route of administration from IVIG), the monthly equivalent of the previously administered IVIG dose at a more frequent dosing interval (once daily to every 2 weeks). Conventional SCIG provides higher steady-state trough levels and less fluctuation between peak and trough levels of IgG than IVIG. The dosing scheme for fSCIG 10% is the same as for IVIG, except that an initial dose ramp-up period is required for fSCIG 10%. There is limited clinical evidence to support the use of conventional SCIG or fSCIG 10% in Ig-naive patients with PIDs; however, model-based simulations indicate that a loading dose preceding the long-term maintenance dose is required to enable rapid attainment of adequate serum IgG levels.

7. Future perspective

Given the advantages and disadvantages associated with each route of administration, and that the optimal dose and dosing frequency of IgGs remains under debate, there are opportunities for further research to investigate the optimization of the IgG therapy dosing paradigm in patients with PIDs, especially in IgG-naive patients. The areas of interest are summarized below.

7.1. Conventional SCIG dosing strategy following a switch from IVIG

Whether there are truly clinical benefits of using a dose conversion factor is still up for debate, given the differences in regional labels.

7.2. Assessing therapeutic benefit of IgG

At present, there are still gaps in understanding as to whether serum IgG trough levels, or maximum concentrations, or both, are essential for determining the therapeutic benefit of IgGs in patients with PIDs. However, it is widely believed that trough levels should be considered as a therapeutic marker and conceptually, this appears to be correct because PIDs are characterized by Ig deficiency. Validation studies could be conducted using data from clinical trials to test this assumption.

7.3. Variability in PK and response to IgG therapy

Current clinical studies indicate that there is substantial variability in the PK and response to IgG therapy in PIDs. The extent of this variability needs to be established and understood further as individualized therapy is likely to prove to be of immense therapeutic benefit to patients with PIDs. Individualized dosing strategies should ensure that no patient receives unnecessarily high or subtherapeutic doses of IgGs.

7.4. Ig-naive patients

To date, limited clinical evidence has been reported in this patient population. Despite the exciting body of data being generated from model-based simulations, dedicated clinical studies in the Ig-naive PID patient population are needed to confirm the results from these simulations.

Funding Statement

Open Access publication was funded by Takeda Pharmaceuticals International AG.

Financial disclosure

No funding was provided for this study. Open Access publication was funded by Takeda Pharmaceuticals International AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

Z Li is an employee of Takeda Development Center Americas, Inc., and is a Takeda shareholder. I Mahmood is a consultant to Takeda Development Center Americas, Inc. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Medical writing services, limited to editing and proof reading, were provided by Jessica Donaldson-Jones, PhD, of Oxford PharmaGenesis Ltd, Oxford, UK and funded by Takeda Pharmaceuticals International AG.