# Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

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## Abstract

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## 1. Introduction

^{−1}, based on the observation that patients with moderate hemophilia (i.e., those with baseline factor levels >1 IU dL

^{−1}) are less prone to the spontaneous bleeds and subsequent arthropathy seen in more severe cases [1]. In a study of 65 boys with severe hemophilia A, only regular prophylactic infusions were shown to prevent joint damage as compared to on-demand treatment [2]. While there is global unanimity that prophylaxis should be initiated before joint disease is sustained [3,4], the implementation of this approach is quite variable [5]. No optimal dosing regimen has been identified; instead, an individualized approach that accounts for the patient’s physical activity, current (and accepted future) musculoskeletal condition, and the availability of resources has been suggested [6,7]. Ideally, the patient’s pharmacokinetic (PK) profile is taken into account to define a truly individualized regimen that optimizes both safety and resource utilization [8]. To facilitate the adoption of PK-based dosing regimens, tools such as the Web Accessible Population Pharmacokinetics Service—Hemophilia (WAPPS-Hemo [9,10]) provide estimates of individual PK parameters from a minimal number of samples by leveraging population PK data. Despite the development of these platforms, the majority of hemophilia patients are still dosed according to total body weight, as initially proposed by Ingram in 1981 [11]. For instance, hemophilic children in Canada are started on a once-weekly regimen (50 IU kg

^{−1}), then step up to either twice weekly (30 IU kg

^{−1}) or every 48 h (25 IU kg

^{−1}) as required; prophylaxis regimens in the Netherlands (Utrecht protocol: 15–30 IU kg

^{−1}three times per week) and Sweden (Malmö protocol: 25–40 IU kg

^{−1}three times per week), though proposing different intensities and targeting different levels, are based on the same principle [12].

^{−1}/IU kg

^{−1}is assumed. For example, a desired increase to normal FVIII levels (100%) would lead to a 50 IU kg

^{−1}dose being administered. However, the assumption that IVR equals 2 for all is not always valid. A study by Henrard et al. found that overweight patients (BMI > 29.6 kg·m

^{−2}) had a median IVR of 2.70, while underweight patients (BMI < 20.3 kg·m

^{−2}) had a median IVR of 1.60 [17].

^{−1}) [21]. Since vasculature represents a very small fraction (0.005–0.010) of adipose tissue volume [22], an excess (or scarcity) of fat does not significantly alter the volume of distribution of FVIII. As a result, overweight and obese patients are likely overdosed when dose is calculated using total body weight [23]. A similar issue has been noted for dosing of unfractionated heparin, another compound whose volume of distribution is approximately equal to the plasma volume; obese children achieved comparable anticoagulation at a lower weight-based dose [24]. Hemophilia treatment is expensive, with annual costs in the hundreds of thousands for those on prophylaxis [2], and while prophylaxis does achieve better health outcomes, these come at a significant cost that is not automatically offset by prevention of other expenses [25]. As the clotting factor itself represents the majority of the cost of prophylaxis [26], overdosing can introduce a significant waste of resources [27]. This study will explore alternative dosing regimens that optimize both safety and resource utilization in overweight and obese hemophiliacs.

## 2. Methods

#### 2.1. Population Generation

^{−2}); the second group represents an overweight and obese population with BMI between 29.6 kg·m

^{−2}and 40.0 kg·m

^{−2}. These cut-off values for BMI were found to be the strongest predictors of FVIII IVR. Each group contains 1000 simulated subjects with a uniform BMI distribution. Heights were derived from the distribution provided by the NHANES database [28]. A uniform distribution of BMI’s was simulated and the total body weights were calculated as the product of BMI and the square of height.

#### 2.2. Definitions of Weight Metrics

^{−2}):

- Lean body weight (LBW) [29]$$\mathrm{LBW}=\frac{9270\times \mathrm{TBW}}{6680+216\times \mathrm{BMI}},$$
- Ideal body weight (IBW—Lorentz formula)$$\mathrm{IBW}=\mathrm{HT}-100-\left(\frac{\mathrm{HT}-150}{4}\right),$$
- Adjusted body weight (ABW)$${\mathrm{ABW}}_{25}=\mathrm{IBW}+0.25\times (\mathrm{TBW}-\mathrm{BW}),$$$${\mathrm{ABW}}_{40}=\mathrm{IBW}+0.4\times (\mathrm{TBW}-\mathrm{IBW}).$$

_{25}) and 40% (ABW

_{40}) correction factors. Correlation plots for all body size metrics are presented in Supplementary Figures S1 and S2 for normal and overweight/obese individuals, respectively.

#### 2.3. Population Pharmacokinetic Model

^{®}, Bayer, Leverkusen, Germany), built on 183 subjects. Of the 109 patients above 18 years of age, the BMI range was 15.0–38.3 kg∙m

^{−2}. The details of the model structure are presented in Table 1. For each simulated individual, PK parameters were calculated. Each virtual individual was then dosed based on various weight metrics and their PK was simulated.

#### 2.4. Simulation and Assessment of Treatment Regimens

^{−1}. FVIII levels were simulated using time steps of 0.2 h following dosing regimens for four weeks to ensure that steady state was reached, and results from the 5th week were used in subsequent analysis steps. In a first instance, we analyzed a typical dosing strategy (20 IU kg

^{−1}TBW every 48 h) to evaluate its appropriateness.

^{−1}for each weight metric (10 IU kg

^{−1}of TBW, 10 IU kg

^{−1}of LBW, etc.) up to 210 IU kg

^{−1}. Initially, the dose step was 2 IU kg

^{−1}for doses up to 100 IU kg

^{−1}and 10 IU kg

^{−1}for doses between 100 and 210 IU kg

^{−1}. After reviewing the results, the dose step was reduced to 0.1 IU kg

^{−1}between 20 and 30 IU kg

^{−1}, as this was the range of most interest. A regimen was considered to be safe for a BMI group if 95% of the simulated population within that group had factor levels above 1 IU dL

^{−1}at all times (C

_{min}≥ 1 IU dL

^{−1}). The lowest dose per weight metric that met this safety criterion was identified and considered to be the optimal regimen for that particular metric and BMI group. A secondary measure of safety was the 95th quantile for time spent below 1 IU dL

^{−1}; in other words, the amount of time per week spent below trough for the 5% of the population not meeting the safety criteria. To evaluate economic differences between regimens, we calculated the mean weekly consumption on each optimal regimen to determine which dosing regimen met safety requirements while minimizing resource expenditure. This process was then repeated for a Monday-Wednesday-Friday (M-W-F) dosing schedule. For these simulations, the optimal dose for each metric (determined in the previous simulations) was administered on Monday and Wednesday, and the Friday dose was increased until the safety criterion was reached. To evaluate the importance of the earlier assumption of 0.5 IU dL

^{−1}baseline, we repeated the above simulations assuming a baseline of 0 IU dL

^{−1}to observe if similar trends emerged.

## 3. Results

^{−1}TBW every 48 h were completed and the results are summarized in Table 2. We then investigated the hypothesis that a TBW-based dosing regimen results in overdosing in overweight and obese patients by determining the TBW-based dose required to meet the 1 IU dL

^{−1}safety criterion in 95% of these patients. At a dose of 20 IU kg

^{−1}TBW, the median minimum concentration (C

_{min}) throughout the week for these patients was 5.4 IU dL

^{−1}; the average consumption associated with this dosing regimen was 7.25 × 10

^{3}IU per person per week. However, this population requires only 14 IU kg

^{−1}TBW to meet the 95% safety criterion, which corresponds to an average weekly consumption of 5.07 × 10

^{3}IU per person.

^{−1}of each weight metric on a Q48 h dosing schedule. Once steady state was reached, the percentage of patients with C

_{min}≥ 1.0 IU dL

^{−1}was calculated. If this percentage was below 95%, the dose was incrementally increased until this threshold was reached. We then calculated the mean weekly consumption associated with the minimum dose required to reach the safety criterion for each metric to assess cost-effectiveness. Since a Monday-Wednesday-Friday dosing schedule is commonly used in hemophilia A prophylaxis, we performed analogous simulations using this schedule instead of a regular 48 h interval. We used the optimal doses found in the previous study on Monday and Wednesday, and then increased the dose on Fridays to compensate for the longer interval until the safety criterion was met.

^{−1}. The most appropriate regimen is the one that meets the safety requirements while consuming the least amount of factor concentrate. For patients within the normal BMI range, LBW produced the optimal regimen for both dosing schedules; for the overweight and obese cohort, an IBW-based dosing regimen was found to be most cost-effective. Furthermore, the range of mean weekly consumption across the various weight metrics was much tighter for the normal BMI subgroup (125 IU per person per week) as compared to the overweight/obese subgroup (483 IU per person per week). When the two subgroups were combined, ABW with a 25% correction factor proved to be ideal for the Q48 h regimen, with IBW a very close second with a difference of just 5 IU per person per week. Both ABW

_{25}and IBW perform almost identically in terms of safety for both BMI subgroups for the Q48 h regimen (Figure 2). However, IBW performed better than all other weight metrics when a Monday-Wednesday-Friday schedule was adopted, with a difference in consumption of over 100 IU per person per week when compared to the next best metric (LBW). Nevertheless, the amount of time spent below 1 IU dL

^{−1}is significantly greater when following a Monday-Wednesday-Friday regimen as compared to the Q48 h dosing schedule (Figure 3b); additionally, an extremely high Friday dose (>125 IU kg

^{−1}TBW) is required to meet the 95% safety requirement, whereas a dose of 18 IU kg

^{−1}TBW is successful for the Q48 h regimen (Figure 3a).

^{−1}. The safety ratio versus dose curves are once again nearly identical for both BMI subgroups (Figure 4), although consumption was approximately doubled as compared to the Q48 h regimen.

## 4. Discussion

^{−1}TBW, Q48 h regimen in an overweight and obese patient population. For comparison, we determined the TBW-based dose required to meet the safety criterion. At a dose of 14 IU kg

^{−1}TBW, 95% of patients had FVIII levels of at least 1 IU dL

^{−1}at all times; the median C

_{min}was 3.9 IU dL

^{−1}and the mean consumption was just over 5000 IU per person per week. By contrast, the 20 IU kg

^{−1}TBW regimen produced a median C

_{min}of 5.4 IU dL

^{−1}with a mean consumption of 7250 IU per person per week. Hence, the standard TBW-based dosing protocol results in over 40% higher consumption than required in the overweight and obese population; assuming a cost of $1 US per unit of concentrate, this amounts to over $100,000 US in excess spending per person annually. From this evaluation, it is clear that TBW does not represent the optimal body weight metric to guide FVIII dosing.

_{25}, and ABW

_{40}) were carried out using the two most common dosing schedules in hemophilia A prophylaxis: a regular 48 h regimen and a Monday-Wednesday-Friday regimen. Adapting a Monday-Wednesday-Friday timetable made it extremely difficult to meet the safety requirement, regardless of which weight metric was used to define the dose. While patients are often advised to increase their FVIII dose on Friday, a simple doubling of the dose is not sufficient. A potentially harmful Friday dose of 140 IU kg

^{−1}TBW was required for 95% of patients to have a C

_{min}≥ 1 IU dL

^{−1}, compared to 18 IU kg

^{−1}TBW to meet this safety minimum when infused every 48 h. Furthermore, the time spent below 1 IU dL

^{−1}(and, consequently, the risk of bleeding events [32]) is significantly greater when following a Monday-Wednesday-Friday regimen, even if the Friday dose is twice or three times greater than the Monday and Wednesday doses (Figure 3b). In fact, a 2010 study in which FVIII was administered three times per week found that over 80% of bleeds occurred 48–72 h post-infusion [33]. The Monday-Wednesday-Friday treatment schedule, while more convenient, is no longer considered to be optimal therapy due to this increased vulnerability to bleeds during the weekend, with alternate day dosing representing the ideal regimen [34,35].

^{−1}[36,37], which is greater than endogenous levels for severe hemophilia patients. To balance both safety and resource utilization, we ran initial simulations with an assumed baseline of 0.5 IU dL

^{−1}. However, it is known that many severe hemophilia patients possess a genetic mutation such that no functional FVIII is produced endogenously. For this reason, the simulations were performed again using a baseline of 0 IU dL

^{−1}to ensure similar trends were observed within this sub-population. Notably, a 95% safe ratio can be achieved in a population with no endogenous FVIII production at a reasonable dose (34 IU kg

^{−1}TBW) if administered every 48 h. However, it is not possible to meet that safety threshold in this population if a Monday-Wednesday-Friday dosing schedule is employed. If the safety criteria is lowered to 90%, it can be met, but only with extremely high Friday doses (between 130 and 180 IU kg

^{−1}for the various weight metrics) and associated weekly consumption (>16,000 IU per person per week); a study by Collins et al. found similarly high doses (>100 IU kg

^{−1}for patients with average half-lives, and up to 400 IU kg

^{−1}in extreme cases) were required to maintain FVIII levels above 1 IU dL

^{−1}throughout the week when following this dosing schedule [38]. These results suggest that a regular dosing interval of 48 h offers significant advantages over the weekly Monday-Wednesday-Friday schedule in terms of both safety and cost-effectiveness.

_{25}producing fairly similar results. Ideal body weight performed almost exactly the same in terms of safety between the normal and overweight groups across all of the doses and regardless of baseline, as evidenced by the closeness of the curves shown in Figure 2 and Figure 4. Further, IBW was the most cost-effective in three out of four simulations; in the fourth, it differed by only 5 IU per person per week from the optimal regimen (ABW

_{25}). If we compare the optimal regimen for a Q48 h schedule with a baseline of 0.5 IU dL

^{−1}(i.e., 20.7 IU kg

^{−1}IBW) to a 20 IU kg

^{−1}TBW, this alterative regimen offers a savings of over 2000 IU per person per week (or nearly $110,000 US annually) for overweight and obese patients. Thus, IBW-based dosing offers a similar safety profile to the currently used TBW strategy while moderating the economic burden of clotting factor prophylaxis.

## 5. Conclusions

_{min}≥ 1 IU dL

^{−1}in 95% of the population, and then the average consumption for each regimen was calculated to evaluate resource-effectiveness. From this study, we conclude that ideal body weight performs the best, maintaining safety while tempering factor consumption for overweight and obese patients.

## Supplementary Materials

## Acknowledgments

## Author Contributions

## Conflicts of Interest

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**Figure 1.**Correlation of body weight metrics with body mass index (BMI) for each BMI subgroup (blue = normal weight, red = overweight and obese). TBW: total body weight; HT: height; LBW: lean body weight; IBW: ideal body weight; ABW: adjusted body weight.

**Figure 2.**Percentage of patients with C

_{min}≥ 1 IU dL

^{−1}(safety) at various doses per kg of various weight metrics, stratified by BMI subgroup, administered at 48-h intervals.

**Figure 3.**(

**a**) Median and 90% confidence intervals for C

_{min}and (

**b**) 95th quantile for time spent below 1 IU dL

^{−1}(hours per week) for TBW-based dosing regimen administered at different intervals for the combined group (normal + overweight/obese) for both Q48 h (blue) and Monday-Wednesday-Friday (red) dosing schedules. For the Q48 h regimen, all doses are increasing along the X-axis; for the Monday-Wednesday-Friday schedule, only the Friday dose is changing (Monday and Wednesday doses are fixed at 20 IU per kg TBW).

**Figure 4.**Comparison of safety profiles for patients simulated with baseline 0.5 IU dL

^{−1}and 0 IU dL

^{−1}for a Q48 h regimen. Safety (%) is the percentage of patients with C

_{min}≥ 1 IU dL

^{−1}at various doses per kg of IBW.

**Table 1.**Details of the model developed by Garmann et al. [31]. CL: clearance; Q: intercompartmental clearance; V

_{1}: volume of the central compartment; V

_{2}: volume of the peripheral compartment; RUV: residual unexplained variability; BSV: between subject variability; LBW: lean body weight.

Parameter | Estimate | Covariate Effect | BSV (%CV) |
---|---|---|---|

CL (dL∙h^{−1}) | 1.88 | ${\mathsf{\theta}}_{\mathrm{CL}}{\left(\frac{\mathrm{LBW}}{51.1}\right)}^{0.610}$ | 37.0 |

Q (dL∙h^{−1}) | 1.90 | ||

V_{1} (dL) | 30.0 | ${\mathsf{\theta}}_{{\mathrm{V}}_{1}}{\left(\frac{\mathrm{LBW}}{51.1}\right)}^{0.950}$ | 11.2 |

V_{2} (dL) | 6.37 | ||

Proportional RUV (%CV) | 26.7 | ||

Additive RUV (IU dL^{−1}) | 1.10 |

**Table 2.**Comparison of the typical 20 IU kg

^{−1}total body weight (TBW) dose and the lowest dose meeting the safety threshold (i.e., 14 IU kg

^{−1}TBW) in overweight and obese patients. Results are presented as median (90% confidence interval).

Measure | Regimen | |
---|---|---|

20 IU kg^{−1} TBW, Q48 h | 14 IU kg^{−1} TBW, Q48 h | |

C_{min} (IU dL^{−1}) | 5.4 (1.2–17.3) | 3.9 (1.0–12.3) |

Consumption (IU per person per week) | 7260 (5730–8780) | 5080 (4010–6140) |

**Table 3.**Summary of safety and economic evaluations of different weight metrics used in a Q48 h regimen across BMI subgroups, assuming a baseline factor level of 0.5 IU dL

^{−1}. Dose is the dose required to have 95% of patients with a steady state C

_{min}over 1 IU dL

^{−1}. Optimal regimens for each subgroup and the overall population are bolded. IBW: ideal body weight, ABW: adjusted body weight.

Metric | Normal | Overweight and Obese | All BMI Categories | ||||
---|---|---|---|---|---|---|---|

Dose (IU kg ^{−1}) | Mean Consumption (IU per Person per Week) | Dose (IU kg ^{−1}) | Consumption (IU per Person per Week) | Dose (IU kg ^{−1}) | Mean Consumption (IU per Person per Week) | Difference in Consumption from TBW | |

TBW | 20.0 | 5202 | 14.0 | 5074 | 18.0 | 5603 | - |

LBW | 25.6 | 5114 | 21.3 | 5028 | 23.8 | 5186 | −417 |

IBW | 22.2 | 5222 | 20.7 | 4828 | 22.1 | 5176 | −427 |

ABW_{25} | 21.7 | 5239 | 20.0 | 5311 | 20.4 | 5171 | −432 |

ABW_{40} | 21.1 | 5173 | 18.0 | 5129 | 20.0 | 5301 | −302 |

**Table 4.**Summary of safety and economic evaluations of different weight metrics used in a Monday-Wednesday-Friday regimen across BMI subgroups, assuming a baseline factor level of 0.5 IU dL

^{−1}. Dose is the Friday dose required to have 90% of patients with a weekly C

_{min}≥ 1 IU dL

^{−1}. Optimal regimens for each subgroup and the overall population are bolded.

Metric | Normal | Overweight and Obese | All BMI Categories | ||||
---|---|---|---|---|---|---|---|

Dose (IU kg ^{−1}) | Consumption (IU per Person per Week) | Dose (IU kg ^{−1}) | Consumption (IU per Person per Week) | Dose (IU kg ^{−1}) | Consumption (IU per Person per Week) | Difference in Consumption from TBW | |

TBW | 74 | 8174 | 54 | 9320 | 62 | 8716 | - |

LBW | 94 | 8082 | 82 | 8740 | 88 | 8442 | −274 |

IBW | 78 | 8213 | 84 | 8543 | 80 | 8312 | −404 |

ABW_{25} | 78 | 8195 | 72 | 8558 | 76 | 8459 | −258 |

ABW_{40} | 76 | 8126 | 68 | 8792 | 72 | 8481 | −235 |

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

## Share and Cite

**MDPI and ACS Style**

McEneny-King, A.; Chelle, P.; Henrard, S.; Hermans, C.; Iorio, A.; Edginton, A.N.
Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis. *Pharmaceutics* **2017**, *9*, 47.
https://doi.org/10.3390/pharmaceutics9040047

**AMA Style**

McEneny-King A, Chelle P, Henrard S, Hermans C, Iorio A, Edginton AN.
Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis. *Pharmaceutics*. 2017; 9(4):47.
https://doi.org/10.3390/pharmaceutics9040047

**Chicago/Turabian Style**

McEneny-King, Alanna, Pierre Chelle, Severine Henrard, Cedric Hermans, Alfonso Iorio, and Andrea N. Edginton.
2017. "Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis" *Pharmaceutics* 9, no. 4: 47.
https://doi.org/10.3390/pharmaceutics9040047