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J.A. Abrantes et al.
individual PK parameters, a patient-specific dosing regi- men can be suggested.13 Recently, the shift from standard prophylaxis to PK-based prophylaxis was facilitated by the development of dosing tools, which are hemophilia- specific for one (e.g. my PKFit, Shire Pharmaceutical Holdings Ireland Limited, Dublin, Ireland; www.mypkfit.com) or multiple (WAPPS-Hemo, McMaster University, Hamilton, Ontario, Canada, www.wapps- hemo.org) FVIII products, or generic tools (e.g. DoseMe LLC, Taringa Qld, Australia; www.doseme-rx.com; InsightRX Inc., San Francisco, CA, USA, www.insight- rx.com), which also support drugs from other clinical areas.14
The choice of individual dosing regimens in PK-based prophylaxis is based on information about the individual PK, but is also based on other components such as the patient’s bleeding pattern, joint status or physical activity. From a PK perspective, the dose and dosing interval that generates an individual trough plasma FVIII activity above a certain target level, traditionally 1 IU/dL, is select- ed.1,15 However, even though this level was not supposed to be an end in itself,16 but rather an orientation, until recently it was the main target used to build prophylaxis regimens. Several studies showed that some patients still bleed with higher trough values, while others do not bleed despite having trough values below 1 IU/dL, sug- gesting that a “one-target-fits-all” strategy is not appropri- ate.16-22 Other measures of target FVIII exposure have been associated with bleeding,23 and different target levels for different patients that take into consideration individual lifestyle were recently suggested.24
One of the most important clinical endpoints to assess efficacy in hemophilia is bleeding frequency. This is often reported as the absolute number of bleeds during the study duration or annualized bleeding rate with the respective dispersion (e.g. range or standard deviation).25 Whereas these bleeding outcome measures may be useful to report efficacy, they are not adequate to study predic- tors of bleeding as they do not account for complex aspects, such as individual differences in FVIII disposition or bleeding phenotype, or time-varying factors, such as changes in dosing regimens or bleeding patterns. However, using an integrated model-based analysis over- comes these limitations. Repeated time-to-event model- ing, an extension of parametric time-to-event survival analysis using non-linear mixed effects modeling, accounts for the occurrence of multiple events (e.g. bleeds) within an individual.26,27 This methodology enables the characterization of time-varying patterns in the occurrence of events (e.g. bleeding patterns changing over time) or predictors of events (e.g. FVIII activity) and has successfully been applied to several clinical areas, e.g. to describe the analgesic consumption in postoperative pain,28 or the time to the occurrence of epileptic seizures.29 This technique can be further extended to capture how consecutive events may be related to each other (Markovian dependence), or to include the severity of the events [repeated time-to-categorical event (RTTCE) mod- eling].30
To better understand the link between prophylactic FVIII replacement therapy and bleeding patterns in patients with severe hemophilia A, the aim of this study was to characterize the relationship between FVIII doses, FVIII activity in plasma, and the occurrence of bleeds, as well as bleeding severity (mild, moderate or severe).
Methods
For a detailed description of the methods used, see the Online Supplementary Appendix.
Patients and data
This post-hoc analysis was based on dosing, PK, bleeding and patient characteristics data obtained from the three LEOPOLD tri- als (LEOPOLD I clinicaltrials.gov identifier: 01029340, LEOPOLD II clinicaltrials.gov identifier: 01233258 and LEOPOLD kids clinicaltri- als.gov identifier: 01311648),31-33 evaluating efficacy, safety and PK of a full-length recombinant human FVIII product, BAY 81-8973 (octocog alfa, Kovaltry®),34 in severe hemophilia A (endogenous FVIII activity <1 IU/dL) patients. Previously treated patients with no history of FVIII inhibitors, receiving on-demand or prophylac- tic treatment at screening, aged 12-64 years (LEOPOLD I and II) and ≤12 years (LEOPOLD kids) were included. Single doses of 50 IU/kg or 20-50 IU/kg 2-3 times/week (LEOPOLD I), 20-40 IU/kg 2-3 times/week (LEOPOLD II), and 25-50 IU/kg at least 2 times/week (LEOPOLD kids) were administered. The study pro- tocols were reviewed and approved by each site’s independent ethics committee or institutional review board.
Factor VIII activity was measured by the chromogenic assay. Bleeding episodes observed during prophylactic treatment were included in the analysis, which included spontaneous, trauma- related and untreated bleeds (i.e. bleeds not requiring FVIII infu- sions in addition to scheduled treatment), and unspecified events requiring FVIII treatment. Date and time of injection, and bleeding data (date, time, severity and location) were self-reported by the patient or caregiver using an electronic patient diary. A maximum of one bleed per calendar day was recorded, and spontaneous joint or muscle bleeds were not registered if occurring within 72 hours (h) of another bleed at the same site or respective infusion.
Model development and assessment
Model estimation was performed using non-linear mixed effects modeling in NONMEM® 7.4.3.35 The PK and RTTCE mod- els were estimated simultaneously and covariates integrated after- wards. Model assessment was based on scientific plausibility, changes in the objective function value (OFV, -2·log-likelihood), goodness-of-fit plots and precision of parameter estimates. For nested models, the likelihood ratio test was used [difference in OFV (DOFV) >6.64 considered significant at =0.01, 1 d.f.].
Population pharmacokinetic model
The population PK analysis started from the model by Garmann et al. using the corresponding set of data.36 The included associa- tion between lean body weight (LBW) and clearance (CL) and cen- tral volume of distribution (V1) was retained given the wide age range of patients. The previous model assumptions were compre- hensively assessed.
Repeated time-to-categorical bleed model
The probability density of each bleed, as well as the probability associated with each severity was estimated from the observed time of bleeding and severity score (mild, moderate, severe) using a combination of parametric survival analysis and proportional odds model for ordered categorical data,26,27,37,38 i.e. the RTTCE model.30 The distribution of time of bleeds was explored using exponential, Weibull and Gompertz hazard functions. Inter-indi- vidual variability was considered on the overall bleeding hazard and on the logit transform of the severity probability. The censor- ing time for bleeds was set at the end of the individual bleeding observation period (right-censored observation).
The influence of individual plasma FVIII activity predicted from
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