Daniel E. Vaughn

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.

Accelerated Insulin Pharmacokinetics and Improved Postprandial Glycemic Control in Patients With Type 1 Diabetes After Coadministration of Prandial Insulins With Hyaluronidase

OBJECTIVE To compare the pharmacokinetics, pharmacodynamics, and safety of insulin lispro or regular human insulin (RHI) with or without recombinant human hyaluronidase (rHuPH20) administered before a standardized meal. RESEARCH DESIGN AND METHODS In this four-way, crossover study, 22 patients with type 1 diabetes received injections of individually optimized doses of lispro or RHI with and without rHuPH20 before a liquid meal. RESULTS With rHuPH20 coadministration, early insulin exposure (0–60 min) increased by 54% (P = 0.0011) for lispro and 206% (P < 0.0001) for RHI compared with the respective insulin alone. Peak blood glucose decreased 26 mg/dL for lispro (P = 0.002) and 24 mg/dL for RHI (P = 0.017), reducing hyperglycemic excursions (area under the curve for blood glucose >140 mg/dL) by 79% (P = 0.09) and 85% (P = 0.049), respectively. Rates of hypoglycemia were comparable for lispro with or without rHuPH20, whereas coadministration of RHI and rHuPH20 reduced hypoglycemia. CONCLUSIONS Lispro or RHI with rHuPH20 produced earlier and greater peak insulin concentrations and improved postprandial glycemic control.

Review of the Mechanism of Action and Clinical Efficacy of Recombinant Human Hyaluronidase Coadministration with Current Prandial Insulin Formulations

For patients with type 1 or type 2 diabetes, achieving good glycemic control is critical for successful treatment outcomes. As many patients remain unable to reach glycemic goals with currently available rapid-acting analog insulins, ultrafast insulin products are being developed that provide an even faster pharmacokinetic Profile compared with current rapid prandial insulin products. The overall strategy of these ultrafast insulin products is to better mimic the normal physiologic response to insulin that occurs in healthy individuals to further improve glycemic control. Recombinant human hyaluronidase (rHuPH20) is a genetically engineered soluble hyaluronidase approved by the U.S. Food and Drug Administration as an adjuvant to increase the absorption and dispersion of other injected drugs; mammalian hyaluronidases as a class have over 6 decades of clinical use supporting the safety and/or efficacy of hyaluronidase coadministration. Clinical findings have demonstrated that coadministration of rHuPH20 with insulin or an insulin analog achieved faster systemic absorption, reduced inter- and intrapatient variability of insulin absorption, and achieved faster metabolic effects compared with injection of either insulin formulation alone. The magnitude of this acceleration is similar to the incrementally faster absorption of prandial insulin analogs as compared with regular insulin. In addition, coadministration of rHuPH20 with regular insulin or insulin analog also improved the achievement of prandial glycemic targets. Thus, rHuPH20 coadministration shows promise as a method of establishing a more rapid insulin Profile to prandial insulin in patients with diabetes and has the potential to yield substantial improvements in postprandial glycemic excursion.

Comparative Pharmacokinetics and Insulin Action for Three Rapid-Acting Insulin Analogs Injected Subcutaneously With and Without Hyaluronidase

OBJECTIVE To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20). RESEARCH DESIGN AND METHODS This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20. RESULTS The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123–131 min and 50% total glucose infused at 183–186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71–79 min and 50% glucose infused at 127–140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action. CONCLUSIONS Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action.

Use of recombinant human hyaluronidase to accelerate rapid insulin analogue absorption: experience with subcutaneous injection and continuous infusion.

OBJECTIVE To discuss clinical studies in which recombinant human hyaluronidase (rHuPH20) was used to increase insulin dispersion and accelerate its absorption. METHODS We reviewed 10 pertinent clinical studies, 8 of which had data available. RESULTS In 4 euglycemic clamp studies, coinjection of rHuPH20 consistently yielded acceleration of insulin absorption, providing twice the insulin exposure during the first hour, greater and earlier peak exposure, and half the exposure beyond 2 hours after injection. Insulin-action profiles were similarly accelerated, with a 15-minute faster onset of insulin action and a 45-minute shorter duration of action for each of the 3 commercial rapid-acting insulin analogues. Infusion aspart insulin formulated with rHuPH20 also accelerated insulin absorption and action over the infusion set life when delivered by insulin pump. Administration of rHuPH20 reduced the inconsistency of insulin absorption and action profiles attributable to 3 factors-lack of reproducibility after identical injections, differences across insulin dose ranges, and changes over infusion site life. The rHuPH20-facilitated ultrafast profile consistently reduced hyperglycemic excursions both in injections immediately preceding liquid test meals and in bolus infusions immediately before solid test meals. rHuPH20-facilitated insulin administration has been well tolerated, with safety and tolerability similar to those with the comparator insulin alone. CONCLUSION rHuPH20 accelerates insulin-action profiles to an extent comparable to the difference between rapid-acting insulin analogue profiles and those of regular insulin. Studies are currently under way to characterize the effect on diabetes management end points (including hemoglobin A1c, blood glucose, and rates of hyperglycemia) of insulin analogues coformulated with rHuPH20 for treatment of both type 1 and type 2 diabetes.

The INFUSE-Morphine study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneously administered morphine in patients with advanced illness.

Morphine is often administered by the subcutaneous (SC) route when venous access is difficult to achieve. Hyaluronidase temporarily increases the permeability of SC connective tissues by degrading hyaluronan and has been shown to increase the dispersion and absorption of coadministered molecules. Therefore, hyaluronidase could enhance the pharmacokinetics of subcutaneous morphine. This Phase IIIB, double-blind, randomized, placebo-controlled crossover study compared the pharmacokinetics, safety, and tolerability of morphine administered SC with and without 150U of recombinant human hyaluronidase (rHuPH20) with those of intravenous (IV) morphine administration in 13 patients in a hospice or palliative care setting. Each patient received morphine 5mg parenterally daily for three days by a different method each day: IV, SC plus rHuPH20, and SC plus placebo (normal saline). The primary endpoint was the time to maximum plasma concentration (T(max)) for morphine. Concomitant SC administration of rHuPH20 enhanced the absorption rate of morphine compared with SC morphine with placebo, significantly reducing the mean T(max) from 13.8 to 9.2 minutes, a 33% decrease (P=0.026). The respective values for geometric mean maximum plasma concentration were 94.9 and 107.5nmol/L, a 13% increase (P=0.024), and the area under the plasma concentration vs. time curve values were 7.7 and 7.2micromol x min/L (P=0.23). Morphine plus rHuPH20 appeared to be safe and well tolerated. In patients requiring opioid analgesia, SC morphine plus rHuPH20 provides pharmacokinetic characteristics that are superior to those of SC morphine alone. These positive results warrant further studies on analgesic efficacy of morphine delivered with rHuPH20.

Accelerating and improving the consistency of rapid-acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase.

Rapid-acting insulin analogs were introduced to the market in the 1990s, and these products have improved treatment of diabetes by shortening the optimum delay time between injections and meals. Compared with regular human insulin, rapid-acting insulin formulations also reduce postprandial glycemic excursions while decreasing risk of hypoglycemia. However, the current prandial products are not fast enough for optimum convenience or control. Recombinant human hyaluronidase (rHuPH20) has been used to increase the dispersion and absorption of other injected drugs, and in the case of prandial insulin analogs, it confers both ultrafast absorption and action profiles. Animal toxicology studies have demonstrated excellent tolerability of rHuPH20, and human studies, involving over 60,000 injections of prandial insulin + rHuPH20 to date, have similarly shown excellent safety and tolerability. Studies using rapid-acting analog insulin with rHuPH20 have included clinic-based pharmacokinetic and glucodynamic euglycemic glucose clamp studies, test meal studies, and take-home treatment studies. Administration methods have included subcutaneous injection of coformulations of rapid-acting insulin + rHuPH20 as well as continuous subcutaneous infusion of coformulations or use of pretreatment of newly inserted infusion sets with rHuPH20 followed by standard continuous subcutaneous insulin infusion therapy. These studies have demonstrated acceleration of insulin absorption and action along with improvement in postprandial glycemic excursions and reduction in hypoglycemia risks. Further, rHuPH20 reduces intrasubject variability of insulin absorption and action and provides greater consistency in absorption and action profiles over wear time of an infusion set. Further studies of rHuPH20 in the take-home treatment setting are underway.

Improved postprandial glycemic control in patients with type 2 diabetes from subcutaneous injection of insulin lispro with hyaluronidase.

BACKGROUND Coinjection of hyaluronidase has been shown to accelerate insulin absorption in healthy volunteers and patients with type 1 diabetes mellitus. This study was undertaken to compare the postprandial glycemic response of patients with type 2 diabetes mellitus (T2DM) administered insulin lispro with and without recombinant human hyaluronidase (rHuPH20) and regular human insulin (RHI) with rHuPH20. METHODS This double-blind three-way crossover study compared the insulin pharmacokinetics and glucodynamic response to a standardized liquid meal (80 g of carbohydrate) in 21 patients with T2DM who received subcutaneous injections of individually optimized doses of lispro±rHuPH20 and RHI+rHuPH20. The optimum dose (targeting postprandial glucose [PPG] of 70-140 mg/dL) of each preparation was selected by the investigator following a fixed-dose escalation procedure in three dose-finding meals. RESULTS Co-injection of lispro+rHuPH20 accelerated pharmacokinetics relative to lispro alone (time to peak insulin concentration, 43 vs. 74 min; P=0.0045) with increased exposure in the first hour (184% of control; P<0.0001) and reduced exposure after 2 h (67% of control; P=0.0001). These accelerated pharmacokinetics improved both total hyperglycemic excursions (area under the curve for 0-4 h >140 mg/dL, 56% of control; P=0.048) and hypoglycemic excursions (area under the curve for 0-8 h <70 mg/dL, 34% of control; P=0.033), allowing over three times as many patients to reach the American Diabetes Associations target of peak PPG <180 mg/dL without requiring glucose treatment for hypoglycemia. The mean optimum dose of lispro was reduced 8% from 0.275 U/kg without rHuPH20 to 0.254 U/kg with rHuPH20 (P=0.04). RHI+rHuPH20 had responses and optimum doses comparable to insulin lispro alone. All insulin preparations were well tolerated. CONCLUSIONS Lispro+rHuPH20 provided superior control of glycemic excursion compared with lispro alone, with lower insulin requirements and reduced hypoglycemic excursions.

Reduction in intrasubject variability in the pharmacokinetic response to insulin after subcutaneous co-administration with recombinant human hyaluronidase in healthy volunteers.

BACKGROUND This study was designed to test the hypothesis that co-administration of recombinant human hyaluronidase (rHuPH20) with regular insulin or insulin lispro will reduce intrasubject variability in pharmacokinetic end points compared with lispro alone. METHODS Healthy adult volunteers (18-55 years old) were enrolled in this phase 1, randomized, double-blind, crossover study. Subjects were administered two injections, each on a separate occasion, of three treatments during six euglycemic clamps. Treatments were 0.15 U/kg insulin lispro, 0.15 U/kg insulin lispro with 5 μg/mL rHuPH20, and 0.15 IU/kg regular insulin with 5 μg/mL rHuPH20. Insulin formulations were administered at a concentration of 40 U/mL. Serum immunoreactive insulin levels, blood glucose concentration, and glucose infusion rate determinations were made at baseline and for approximately 8 h after study drug administration. Intrasubject variability was assessed using a general linear mixed model with a fixed effect for treatment using a compound symmetric covariance matrix. RESULTS Co-injection of rHuPH20 with lispro significantly reduced intrasubject root mean square differences in time to peak serum insulin, time to early 50% peak serum insulin (t(50%)), and time to late t(50%) levels compared with lispro alone. Also, the intrasubject coefficient of variation for percentage of total area under the plasma concentration-versus-time curve for early time intervals compared with lispro alone was reduced. Intrasubject variability for regular insulin with rHuPH20 for most pharmacokinetic parameters was similar to the variability of lispro alone, although variability in early exposure was significantly reduced. CONCLUSIONS Co-administration of rHuPH20 with lispro significantly reduced the variability of insulin pharmacokinetics relative to insulin lispro alone.

Benefits of Blinded Continuous Glucose Monitoring during a Randomized Clinical Trial

Background: Real-time, personal continuous glucose monitoring (CGM) is a validated technology that can help patients improve glycemic control. Blinded CGM is a promising technology for obtaining retrospective data in clinical research where the quantity and quality of blood glucose information is important. This study was designed to investigate the use of novel procedures to enhance data capture from blinded CGM. Methods: Following a 4-week run-in, 46 patients with type 1 diabetes were randomized to one of two prandial insulins for a 12-week treatment period, after which they were crossed over to the alternate treatment for 12 weeks. Continuous glucose monitoring was implemented at the end of run-in (practice only) and during the last 2 weeks of each treatment period. Eighty percent of 288 possible daily glucose values were required for at least three days. Continuous glucose monitoring was extended for an additional week if these criteria were not met, and patients were allowed to insert sensors at home when necessary. Continuous glucose monitoring results were compared to reference eight-point self-monitoring of blood glucose (SMBG). Results: Higher than expected sensor failure rate was approximately 25%. During run-in, 12 of 45 attempted profiles failed adequacy criteria. However, treatment periods had only 1 of 82 attempted profiles considered inadequate (6 cases required an additional week of CGM). Using SMBG as reference, 93.7% of 777 CGM values were in Clarke error grid zones A+B. Conclusions: With appropriate training, adequate practice, and opportunity to repeat blinded CGM as needed, nearly 100% of attempted profiles can be obtained successfully.