Accelerated pharmacokinetics and glucodynamics of prandial insulins injected with recombinant human hyaluronidase.

BACKGROUND: This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20). METHODS: Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight >70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C(max)), time to C(max) (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G). RESULTS: For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced t(max) by 51% (P = 0.0006) and 58% (P = 0.0002), increased C(max) by 90% (P = 0.0003) and 142% (P < 0.0001), increased early exposure (AUC(0-2h)) by 85% (P < 0.0001) and 211% (P < 0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P < 0.0001) and 48% (P < 0.0001). Similarly, rHuPH20 reduced tGIR(max) by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P < 0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated. CONCLUSIONS: Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.

pI-shifted insulin analogs with extended in vivo time action and favorable receptor selectivity.

A long-acting (basal) insulin capable of delivering flat, sustained, reproducible glycemic control with once daily administration represents an improvement in the treatment paradigm for both type 1 and type 2 diabetes. Optimization of insulin pharmacodynamics is achievable through structural modification, but often at the expense of alterations in receptor affinity and selectivity. A series of isoelectric point (pI)-shifted insulin analogs based on the human insulin sequence or the GlyA21 acid stable variant were prepared by semi-synthetic methods. The pI shift was achieved through systematic addition of one or more arginine (Arg) or lysine (Lys) residues at the N terminus of the A chain, the N terminus of the B chain, the C terminus of the B chain, or through a combination of additions at two of the three sites. The analogs were evaluated for their affinity for the insulin and IGF-1 receptors, and aqueous solubility under physiological pH conditions. Notably, the presence of positively charged amino acid residues at the N terminus of the A chain was consistently associated with an enhanced insulin to IGF-1 receptor selectivity profile. Increased IGF-1 receptor affinity that results from Arg addition to the C terminus of the B chain was attenuated by cationic extension at the N terminus of the A chain. Analogs 10, 17, and 18 displayed in vitro receptor selectivity similar to that of native insulin and solubility at physiological pH that suggested the potential for extended time action. Accordingly, the in vivo pharmacokinetic and pharmacodynamic profiles of these analogs were established in a somatostatin-induced diabetic dog model. Analog 18 (A0:Arg, A21:Gly, B31:Arg, B32:Arg human insulin) exhibited a pharmacological profile comparable to that of analog 15 (insulin glargine) but with a 4.5-fold more favorable insulin:IGF-1 receptor selectivity. These results demonstrate that the selective combination of positive charge to the N terminus of the A chain and the C terminus of the B chain generates an insulin with sustained pharmacology and a near-native receptor selectivity profile.

Pharmacokinetics and hepatic extraction of recombinant human parathyroid hormone, hPTH (1-34), in rat, dog, and monkey.

The pharmacokinetics (PK) and hepatic extraction (E(H)) of human PTH (1-34), hPTH (1-34), were characterized in rat, dog, and monkey, following intraportal (IPO) and intravenous (IV) bolus administration. hPTH (1-34) was administered to Sprague-Dawley rats (2, 10, 100 microg/kg), beagle dogs (3, 6 microg/kg), and rhesus monkeys (6, 30 microg/kg). Serum concentrations of immunoreactive hPTH (1-34) were used to derive PK parameters. IPO bioavailability (F(IPO)) was determined by comparing dose-normalized serum exposure (i.e., AUC(IPO)/AUC(IV)). E(H) was estimated as 1-F(IPO). In all species, greater than dose-proportional increases in exposure (i.e., C(max) and AUC) were observed for both routes. Dose-dependent disposition (i.e., time-average clearance (CL) and half-life (t(1/2)) were observed in all three species. In rats, E(H) values of 71% (2 microg/kg), 35% (10 microg/kg), and <1% (100 microg/kg) were obtained. In dogs, E(H) values of 90% (3 microg/kg) and 66% (6 microg/kg) were obtained. In monkeys, E(H) values of 25% (6 microg/kg) and <1% (30 microg/kg) were observed. In conclusion, hPTH (1-34) is subject to hepatic first pass extraction in rat, dog, and monkey with evidence of saturation in the rat. Saturable hepatic extraction in dog and monkey is inconclusive due to the limited dose range investigated.