Enhancing Patient Flexibility of Subcutaneous Immunoglobulin G Dosing: Pharmacokinetic Outcomes of Various Maintenance and Loading Regimens in the Treatment of Primary Immunodeficiency

Patients with primary immunodeficiency (PID), including those with common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), are predisposed to recurrent and persistent infections [1‐7]. Immunoglobulin G (IgG) replacement therapy provides an effective prophylaxis, and for 30 years, monthly intravenous immunoglobulin (IVIG) has been the standard treatment. However, subcutaneous immunoglobulin (SCIG) given at weekly or biweekly (i.e., every 2 weeks) intervals has become an increasingly popular alternative, which has been boosted by the development of increasingly concentrated formulations (as high as 20%) enabling reduced infusion volumes and increased infusion rates [8‐21].

By comparison with monthly IVIG infusion, patients receiving a weekly SCIG dose experience similar protection and infection rates, but demonstrate increased consistency in steady-state IgG levels (reduced peak/trough variation) and suffer fewer systemic adverse events [9, 15, 16, 22‐24]. In addition, SCIG preparations can be self-administered at home by most patients. This reduces treatment cost and increases patient convenience, reflected by a measured improvement in patient quality of life [25, 26].

Subcutaneous immunoglobulin regimens typically divide the total monthly IgG dose into 4 weekly infusions. However, greater patient convenience would be achieved by increasing the flexibility of the dosing regimen and enabling individualized dosing schedules. A few clinical trials exploring alternative SCIG dosing regimens have been published [27‐29], but testing numerous regimens clinically would be time and cost intensive, and may be burdensome for patients. A powerful approach to test a broad range of dosing regimens is population pharmacokinetic (PK) modeling and simulation [30‐35]. By implementing PK models based upon existing clinical data, it is possible to simulate the kinetics of IgG following modification of variables defining a dosing regimen.

We recently developed and validated a population PK model to predict IgG concentration metrics for SCIG and IVIG dosing [36]. Model-based simulations pharmacokinetically supported that a switch from weekly SCIG to biweekly SCIG infusion at double the weekly dose maintained equivalent plasma IgG levels. The biweekly dosing regimen has recently been approved by both the US Food and Drug Administration and the European Medicines Agency for Hizentra^® (20% SCIG; CSL Behring AG, Bern, Switzerland) based on this modeling and simulation [37, 38]. The aim of this investigation was to use the same model to make a broader range of predictions to address the flexibility of SCIG administration. First, the model was used to predict IgG kinetics following dosing regimens ranging from daily to monthly administrations, including the influence of skipped doses. Second, various loading regimens were simulated to measure the time to steady-state IgG concentrations in treatment-naïve patients commencing SCIG therapy.

This article does not contain any new studies with human or animal subjects performed by the authors.

Infused IgG has an elimination half-life of approximately 36 days [40]. Therefore, any dosing regimen with a frequency greater than monthly administration appears feasible from a PK point of view. While the recommended dosing for SCIG is weekly or biweekly administration, more frequent dosing regimens (up to daily) have been adopted by some patients [27, 28]. To assess the IgG kinetics for dosing regimens of higher and lower frequency than weekly dosing, we used a previously validated PK model to simulate events [36]. PK model-based simulations indicated that so long as the total dose of IgG remained constant, there is little difference in IgG exposure metrics when dosing as frequently as daily and up to biweekly. These data support the effectiveness of the varied dosing regimens already used by some patients.

The clinical advantage of frequent dosing is that serum IgG concentrations are more stable, resulting in somewhat higher IgG trough concentrations and reduced peak-to-trough variation. Due to the lack of low IgG trough levels in the days before the next infusion, patients receiving weekly SCIG therapy do not report the wear-off effects experienced by those receiving IVIG toward the end of the 3- or 4-week interval. Simulations presented here showed that SCIG dosing intervals could be extended to biweekly with minimal influence upon serum IgG concentration, whereas 3-weekly and 4-weekly dosing resulted in divergent C _max and C _min values. For this reason, and in terms of maintaining relative equivalency to weekly dosing, we recommend dosing regimens from daily to biweekly (in which the same weekly total dose is administered), but would not recommend dosing intervals from 3-weekly and beyond. Although this reasoning is somewhat subjective, a further consideration concerning the extension of the dosing interval is that greater subcutaneous injection volumes are required, which can become uncomfortable. However, given the variability of IgG half-life among individuals, a 3-weekly or 4-weekly regimen maybe suitable for some patients requiring a rather low dose. Flexibility in the dosing regimen from daily to biweekly enables patients to choose a regimen based on convenience or lifestyle. Possibly this can also improve compliance.

Clear benefits exist for patients offered individualized dosing regimens, tailored to their convenience. Conventional SCIG administration is by infusion pump. However, push administration, using a syringe and butterfly needle, offers a simple alternative at a lower cost (no requirement for a pump). This technique is more suited to frequent administration of lower dose volumes. Retrospective analyses have shown that push administration is preferred by patients as an easier and more convenient approach [26, 27]. In these studies, patients chose to dose on average every 2–3 days regardless of administration procedure, showing that even when patients were administering IgG by pump, they had a preference for a frequent dosing schedule. Some patients administering by pump also reported feeling better when infusing smaller volumes more frequently, although, this may be anecdotal [27].

There is also some flexibility within the dosing regimens as demonstrated by the small impact of 2–3 skipped doses on IgG levels during daily dosing, so long as the doses skipped are compensated for. These data show that if for whatever reason patients are unable to adhere strictly to their dosing regimen, it is simple and practical to compensate. For patients on a weekly or biweekly dosing regimen, trough IgG levels also recovered rapidly upon replacement of skipped doses. However, there is a greater impact on IgG trough levels when doses are skipped on these less frequent regimens, with a risk of IgG levels dropping below a protective level. It would, therefore, not be recommended to skip more than a single dose on a weekly regimen. In addition, the extra volume required to replace these doses during the following infusion could be an issue. By contrast, a double dose before a planned skipped dose had a minimal impact on the trough IgG levels for both weekly and biweekly dosing regimens. Therefore, this would be a feasible option for patients for whom on certain occasions it may be inconvenient to maintain their usual dosing pattern. For example, patients who are traveling or on vacation may take advantage of this option.

If skipped doses are not compensated when the regular daily dosing is resumed, it takes up to 5–6 weeks to return to steady-state levels. For patients with low IgG levels, or who require higher IgG levels for protection against infection, skipped doses should be compensated for as soon as possible. However, this practice should be advised for all patients. If doses are repeatedly skipped and not replaced, the deficit will accumulate. Within a few months of consistently missing one or two doses per week on a daily regimen, predicted IgG trough concentrations dropped to levels which may be under-protective. Compliance with the treatment regimen is, therefore, essential.

The data generated to determine the flexibility within dosing regimens were consistent between the two reference models, RM4.0 and RM1.5, for all simulated dosing regimens. These models represent endogenous IgG concentrations of 4 and 1.5 g/L and are reflective of the average endogenous IgG concentrations for predominantly CVID and XLA patient populations, respectively, thereby indicating that the flexibility within the dosing regimens is applicable to both patient populations.

An initial IVIG loading period before SCIG is not always practical and can be more problematic in children and the elderly, where venous accessibility may be an issue. In addition, treatment-naïve patients are more likely to experience adverse events to IVIG during the first and second infusions [41]. However, in treatment-naïve patients, SCIG therapy started at a constant weekly dose may take up to 6 months to achieve steady-state IgG levels [42]. Obviously, achieving adequate IgG concentrations as quickly as feasible is desirable for clinical efficacy. Borte et al. [39] have described a loading regimen, in which the weekly dose of 100 mg/kg was delivered five times during the first week, before adjusting the patient to a weekly dosing regimen. Nearly, all patients achieved IgG concentrations ≥5 g/L by day 12. An additional advantage of this loading regimen is that the loading phase can be used for training the patient in self-administration, the five loading doses being administered under the supervision of a nurse.

IgG concentration above 7 g/L (representing the lower limit of IgG in healthy adults [43, 44]) is considered to provide adequate protection from infection, and was recommended by a Canadian consensus guideline as the minimum IgG trough level to achieve in most patients [45, 46], although it is recognized that some patients may need a higher IgG level [47]. Our simulation data predicted that, in the absence of a loading dose, IgG concentrations of 7 g/L for SCIG dosing would only be attained after a period of 13 weeks if endogenous IgG was 4 g/L, or after more than 24 weeks if endogenous IgG was as low as 1.5 g/L. Three loading regimens were identified, which ensured that IgG concentrations were rapidly raised to protective quasi-steady-state levels. The first of these regimens was the delivery of the weekly dose of 100 mg/kg for 5 consecutive days during the first week of treatment, as also described by Borte et al. [39]. RM4.0 model simulations were highly comparable to these clinical data, and predicted that this would raise IgG concentrations above 7 g/L within 1 week of treatment initiation and thus provide rapid protection against infection for newly diagnosed patients. However, in the RM1.5 model, these levels were reached only after 21 weeks. This loading regimen may, therefore, be suitable for patients with higher endogenous (pre-therapy) IgG levels, such as patients with CVID, but not in patients with more severe disease or lower endogenous IgG, such as XLA. In such patients, a loading regimen of 150 mg/kg IgG administered five times during the first week of treatment, or 100 mg/kg administered five times during each of the first 2 weeks of treatment achieved IgG levels above 7 g/L within 2 weeks. These loading regimens would obviously also work for endogenous IgG levels of 4 g/L.

In addition, less intensive loading schedules of either 100 mg/kg three times a week or 150 mg/kg two times a week, administered over a 2-week period were able to raise IgG levels above 7 g/L within 2 weeks, when endogenous IgG was 4.0 g/L. These loading regimens might serve as alternatives for patients and physicians who prefer to use a less condensed dosing schedule. When determining clinical recommendations for loading dose regimens, non-PK factors related to clinical feasibility should be considered. This includes reaching IgG levels that would adequately protect the majority of the patient population, while considering patients’ convenience with respect to the required frequency of infusions, infusion volume, number of injection sites, and potential dose compliance. With this in mind, the loading dose of five consecutive infusions of 100 mg/kg during the first week, followed by the regular weekly dose of 100 mg/kg might be the most appropriate for the majority of patients.

For patients with low endogenous IgG level, a loading dose of one and a half times the weekly dose of 100 mg/kg administered five times during the first week of treatment may be considered more appropriate. Similar IgG concentration levels obtained by this more intense loading strategy may also be achieved by loading 100 mg/kg for five consecutive infusions during each of the first 2 weeks of SCIG therapy. However, this approach does not appear to offer any clinically important advantage, may place a higher burden upon patients, and is a more costly alternative. Less intense loading schedules of 150 mg/kg two times per week or 100 mg/kg three times per week for two consecutive weeks may still be appropriate for some patients with non-severe initial condition, relatively high endogenous IgG levels, or those who would like to avoid daily infusions for five consecutive days.

For the above reasons, depending upon the baseline IgG level, an SCIG loading regimen of 100 or 150 mg/kg for five consecutive days in the first week of treatment is predicted to quickly elevate the patient’s serum IgG levels to protective quasi-steady-state levels without the need for an initial IVIG loading dose. After the loading period, the SCIG dose can be adjusted on an individual basis dependent upon IgG levels and clinical response.

All simulations presented here were performed with respect to achieving levels around 7 g/L. While this level is probably protective in many patients, it is a somewhat hypothetical value. In practice it is important to identify the individual’s protective ‘biologic IgG level’, above which the patient remains essentially infection free, with the aim of achieving and maintaining this IgG concentration [47]. Dose levels have to be adapted accordingly. For a CVID patient population, we assumed an endogenous IgG concentration of 4 g/L; we did not take into account the functional status of this IgG, which can be compromised [7]. These patients may require a higher ‘biologic IgG level’. In addition, the efficacy of Ig therapy, i.e., the dose required to achieve a given increase in IgG trough levels, varies from patient to patient, making further dose adjustment necessary [48].

If, in a treatment-naïve patient, it can be anticipated that the target IgG trough level is higher than 7 g/L and, as a consequence, the maintenance dose is higher than 100 mg/kg/week, a loading regimen of the planned maintenance dose administered on five consecutive days is appropriate to bring the serum IgG concentration to the target ‘biologic IgG level’ within one week. If, in addition, this patient has a low endogenous IgG, one and a half times the planned maintenance dose administered 5 days in Week 1 may be required.

In considering the dosing regimens assessed in our work, particularly that for loading doses, a limitation to the modeling needs to be noted. The PK model on which the presented simulations were based was derived using data obtained in clinical trial subjects, all of whom had received IgG therapies prior to their study participation. As there was no PK data from IgG treatment-naïve subjects, methodological assumptions had to be made about the status of endogenous IgG levels. We chose to fix endogenous IgG in the model to a value within a range of 1.5–4.0 g/L. Consequently, confirmation of our assessments of various SCIG loading dose possibilities is warranted. However, the endogenous IgG level limitation is of much lesser importance for our assessments of various SCIG maintenance regimens, whereby a fixed endogenous level was held constant between comparative dosing regimens.

PK modeling predicts that similar IgG concentrations are achieved with a dosing frequency of every 2 weeks or less, so long as the cumulative total dose remains consistent. IgG levels of 7 g/L are achievable in treatment-naïve patients with several SCIG loading regimens during the first 1–2 weeks of SCIG treatment and would provide greater convenience for patients with PID.