Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice - PubMed (original) (raw)

Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice

Yan Weng et al. PLoS One. 2015.

Abstract

Pharmacological administration of fibroblast growth factor 21 (FGF21) improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB)/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (s.c.) bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability). Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW) loss and glucose reduction during an oral glucose tolerance test (OGTT) following SC and intravenous (i.v.) administration in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits.

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Conflict of interest statement

Competing Interests: All authors were employees of Pfizer during the completion and analyses of these studies. Pfizer has provided all funding for these studies. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1

Fig 1. Plasma concentration-time curves of PF-05231023 intact CT and NT.

Plasma concentration-time curves of PF-05231023 in DIO mice following a single IV and SC administration at 10 mg/kg. 3 animals were used per time point. n = 3 animals were used for the 10 mg/kg IV and n = 4 animals were used for the rest of the groups.

Fig 2

Fig 2. Glucose lowering during OGTT in ob/ob mice upon IV and SC administration of PF-05231023.

Male ob/ob mice approximately 9 weeks of age were administered PF-05231023 IV (a) or SC (c) and OGTT was performed 72 hours later, after an overnight fast. At least 8 mice were used per dose group for the OGTTs. Area under the curve during OGTT after IV (b) or SC (d) administration of PF-05231023. 8 animals were used per group. * p < 0.05, ** p < 0.01, and *** p < 0.001 using one-way Anova with Dunnett’s post hoc test.

Fig 3

Fig 3. Glucose lowering during OGTT after PF-05231023 administration.

Male ob/ob mice approximately 9 weeks of age were administered 3 mg/kg PF-05231023 SC and OGTT was conducted after an overnight fast on the indicated days. At least 8 animals were used per group per day. * p < 0.05, ** p < 0.01, and *** p < 0.001 using one-way Anova with Dunnett’s post hoc test.

Fig 4

Fig 4. Percentage BW loss in DIO mice following IV and SC administration of PF-05231023.

Male DIO mice at approximately 14 weeks on 60% HFD were administered PF-05231023 IV or SC at the indicated doses on Day 1, 8 and 15. Body weight was measured twice a week throughout the course of the study until day 57. At least 9 animals were used per dose group.

Fig 5

Fig 5. PK and RO time courses for modeled scenarios.

(a,b) Calculated intact (solid line) and N-only (dashed line) following IV (black) or SC (red) administration of 10 mg/kg of PF-05231023. The in vitro potency of the intact molecule is shown in blue, and the estimated in vivo potency of the N-only pool is shown in green. As the model includes linear PK, other doses can be considered by simple shifting of the curves up or down by the relative dose. The results for central compartment levels in the ob/ob mouse model are in (a); the curves for adipose exposure in DIO mice are in (b). (c,d) Calculated receptor occupancy in the central space of ob/ob mice (c) or the adipose space of DIO mice (d) for the 10 mg/kg dose delivered IV (black) or SC (red). The rapid but short-lasting rise in RO following dosing driven by intact molecules is evident, followed by a sustained RO by the N-only molecules.

Fig 6

Fig 6. OGTT modeling in ob/ob mice.

(a) Data and model predictions for OGTT performed 3, 4, 5, and 6 days following single 3 (red) or 10 (blue) mg/kg SC doses of PF-05231023. (b) Day 3 dose response to single 0.03–10 mg/kg PF-05231023 delivered IV (red) or SC (blue) on day 0. Data represented by circles and error bars; model predictions represented by x’s.

Fig 7

Fig 7. BW loss model results in DIO mice.

(a) Optimized model parameter values, as described in the text. (b,c) Data (shapes) and model predictions (curves) for BW changes following three once-weekly doses of PF-05231023 delivered IV (b) or SC (c) starting on day 0. (d) Optimized transfer function (function of ρ and δ; P(RO) in the text) relating the effect on BW changes to receptor occupancy.

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Pfizer Inc. provided funding for this study. The funder provided support in the form of salaries for all authors listed, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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