James R. Woodworth

[Lys(B28), Pro(B29)]-Human Insulin: A Rapidly Absorbed Analogue of Human Insulin

[Lys(B28, Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 and 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clinical studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans. We wanted to evaluate the effect of adding zinc to LYSPRO on its pharmacokinetics and pharmacodynamics. In addition, we compared the pharmacokinetics and pharmacodynamics of LYSPRO and human Regular insulin after subcutaneous injection to those of human Regular insulin given intravenously. Thus, we compared four treatments: solutions of zinc-free LYSPRO given subcutaneously (A), zinc-containing LYSPRO given subcutaneously (B), human Regular insulin given subcutaneously (C), and human Regular insulin given intravenously (D). We gave a 10-U dose of each treatment to 10 healthy (nondiabetic) men during glucose clamps. Serum insulin concentrations peaked more than two times higher (maximum serum insulin level [Cmax], 698 vs. 308 pM, A vs. C) and in < half the time (time to Cmax [Tmax], 42 vs. 101 min, A vs. C) after subcutaneous injection of zinc-free LYSPRO. At the same time, the glucose infusion rate peaked in about half the time (time to maximum glucose infusion rate [TRmax], 99 vs. 179 min, A vs. C) and was slightly but not significantly higher (maximum glucose infusion rate [Rmax], 3.1 vs. 2.2 mmol/min, A vs. C) than that of human Regular insulin. Although the addition of zinc retarded the absorption of LYSPRO slightly (Cmax, 550 vs. 698 pM, B vs. A), zinc-containing LYSPRO retained its distinct profile (Tmax 53 vs. 42 min, B vs. A). LYSPRO displays faster pharmacodynamic action than human Regular insulin when injected subcutaneously

A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation

Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). Methods: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. Results: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m2. The MTD of MTA was 600 mg/m2, with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m2 dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 μg/ml, 40.0 ml/min per m2, 266 μg · h/ml, and 7.0 l/m2, respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. Conclusions: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m2. MTA is a promising new anticancer agent.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

PURPOSE To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers.

Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. Daptomycin was administered as a single 14C-labeled dose (1.0 mg/kg of body weight) and as single doses between 0.5 and 6.0 mg/kg. All doses were intravenous. Antibacterial activity was determined from doses of 2.0, 3.0, 4.0, and 6.0 mg/kg against two strains of Staphylococcus aureus (one methicillin resistant) and one Enterococcus strain. After administration of 14C-labeled daptomycin, recovery of 14C in urine and feces accounted for 83% of the administered dose, with the greatest fraction (78%) appearing in the urine. Specific analysis for daptomycin in both urine and plasma indicated that metabolic products were present in urine, but total 14C in plasma consisted of daptomycin only. Doses between 0.5 and 6 mg/kg were linear, with a limited total body clearance (0.13 to 0.21 ml/min/kg) and a small volume of distribution (0.10 to 0.15 liter/kg). The small volume of distribution may be a factor of the high plasma protein binding (90 to 95%). Renal clearance made up 34 to 54% of total body clearance. Daptomycin demonstrated in vivo antibacterial activity against all three test strains, with the greatest activity observed against methicillin-resistant S. aureus. The predicted MIC for all three strains was approximately 13 micrograms/ml, corresponding to total (bound plus unbound) drug. On the basis of the drugs pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective.

Injection Site Effects on the Pharmacokinetics and Glucodynamics of Insulin Lispro and Regular Insulin

OBJECTIVE The pharmacokinetics and glucodynamics of a new insulin analog, insulin lispro, and regular human insulin were compared and contrasted after subcutaneous administrations in femoral, deltoid, and abdominal injection sites. RESEARCH DESIGN AND METHODS Single 0.2 U/kg doses of insulin lispro and regular insulin were administered to 12 healthy subjects in a six-way randomized crossover fashion. Each dose was given after an overnight fast in one of three injection sites: abdominal, deltoid, or femoral. Study drugs were given during a manual euglycemic glucose clamp. Blood samples were collected over the 12-h clamp for measurement of insulin-reactive components, with pharmacokinetic and glucodynamic measurements derived from these serum insulin and clamp measurements. RESULTS Glucodynamic comparisons between insulin lispro and regular insulin showed a greater maximum infusion rate (Rmax) at an earlier time (TRmax), regardless of injection site. The total glucose infused (Gtot) showed nearly identical values between sites for insulin lispro. Regular insulin showed greater Gtot values from deltoid and femoral injections. When comparisons were made between drugs, regular insulin produced significantly greater Gtot, primarily driven by the increased Gtot from deltoid and femoral injections. Greater maximum serum insulin concentrations (Cmax) were experienced with insulin lispro at earlier times (tmax), regardless of the injection site (P < 0.001). Abdominal administrations produced the greatest Cmax values at the earliest tmax for both regular insulin and insulin lispro. Deltoid and femoral injections had lower Cmax values for both compounds. Shifts also occurred with tmax, although these shifts were much greater with regular insulin than with insulin lispro. Equivalent area under the curve (AUC) values were found when compared between compounds. CONCLUSIONS Slower absorption from deltoid and femoral administrations resulted in an increased duration of action for both regular insulin and insulin lispro when compared to abdominal administration. However, notable increases in the onset of action were only apparent with regular insulin. The consistency with insulin lispro response from abdominal and extremity injection sites allows more potential sites for subcutaneous injection with an assured rapid response.

[Lys(B28), Pro(B29)]-human insulin: effect of injection time on postprandial glycemia.

[Lys(B28), Pro(B29)]‐human insulin (lispro) is an insulin analogue with a reduced capacity for self‐association and faster absorption from subcutaneous injection sites. We hypothesized that administration of lispro closer to a meal would result in better glucose control than that achieved with regular insulin.

Establishment of Time-Action Profiles for Regular and NPH Insulin Using Pharmacodynamic Modeling

OBJECTIVE To provide distinct definitions and quantify the establishment of onset, peak, and duration of action for insulins. RESEARCH DESIGN AND METHODS We administered single subcutaneous doses of 10 U regular insulin to 10 volunteer subjects and 25 U NPH insulin to 6 healthy male volunteer subjects on separate occasions. Each dose was given after an overnight fast during a glucose clamp to maintain an euglycemic state. We measured serum insulin concentrations and glucose infusion rates (GIR) from frequent blood sampling after each treatment. Serum insulin concentrations were related to GIR values at each collection time and a counter-clockwise hysteresis resulted. An effect compartment model was used to simultaneously describe the pharmacokinetics and pharmacodynamics of each insulin and to resolve the hysteresis. RESULTS From the resulting relationship, GIR could then be predicted, with onset and duration of action reflecting the time when effect compartment concentrations initially exceeded then declined below a 10% maximum possible effect (Emax) level. Ninety-five percent confidence intervals were constructed allowing a predictive range of values. For regular insulin, a mean onset of 0.75 h, peak of 2 h, and duration of 6 h was estimated. Mean values were also produced with NPH, with an onset of 3 h, peak of 6–7 h, and a duration of 13 h estimated. CONCLUSIONS This method estimates the onset, peak, and duration of insulin action. Although these estimates were from single doses, we believe they can provide good estimations of insulin activity.

The Action Profile of Lispro Is Not Blunted by Mixing in the Syringe With NPH Insulin

OBJECTIVE To assess the effect of mixing the insulin analog lispro (Humalog) with NPH (Humulin I) before injection on lispros fast, short action profile. RESEARCH DESIGN AND METHODS A total of 12 healthy volunteers received subcutaneous abdominal injections of 0.1 U/kg regular insulin and 0.2 U/kg NPH insulin as follows: lispro and NPH injected separately (treatment group A), lispro and NPH mixed in the syringe up to 2 min before single injection (treatment group B), and human regular insulin and NPH mixed and injected as in group B (treatment group C), on separateoccasions, in random order. Plasma glucose was maintained for 12 h by intravenous 20% glucose. Pharmacokinetic and pharmacodynamic parameters were compared by analysis of variance for repeated measures RESULTS Peak plasma insulin levels (2.6 ± 0.8 vs. 2.2 ± 0.6 vs. 1.9 ± 0.6 ng/ml, P = 0.075),total glucose infused (121.5 ± 32.8 vs. 135.0 ± 49.0 vs. 117.3 ± 39.9 mg · kg−1 · min−1 P = 0.53), and maximum glucose infusion rate (GlRmax) (8.3 ± 0.9 vs. 8.0 ± 1.7 vs. 7.1 ± 2.4 mg · kg−1 · min−1 P = 0.65) were not significantly different between treatments. The times until peak insulin concentrations were similar in treatment groups A and B, but significantly shorter than in treatment group C (0.9 ± 0.3 and 1.2 ± 0.2 vs. 2.0 ± 0.4 h, respectively, P = 0.042). The times until GIRmax were also not different (113.9 ± 41 and 122.0 ± 45 vs. 209.0 ± 51.3 min, , respectively, P = 0.002). The glucose infusion rate (GIR) then fell to 50% GIRmax more quickly in treatment groups A and B than in treatment group C (239.9 ± 40.5 vs. 292.4 ± 133.3 vs. 399.5 ± 78.3, respectively, P = 0.005). CONCLUSIONS The action profile of lispro is not attenuated by mixing lispro with NPH in the syringe immediately before injection. The advantages are available to those individuals who need to combine typesof insulin before injection to achieve optimal diabetes control.

Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.

OBJECTIVE To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg. RESEARCH DESIGN AND METHODS We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of each mixture separated by at least 7 days. Each dose was given after an overnight fast and during a glucose clamp to maintain a euglycemic state. We measured serum insulin and Cpeptide concentrations through frequent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (Cmax), time to maximum insulin concentration (tmax), terminal rate constant (β), area under the curve from 0 to ∞, (AUC x0), and mean residence time (MRT). Pharmacodynamic measurements were summarized from C-peptide concentrations (minimum C-peptide concentration [Cmin], time to minimum C-peptide concentration [tmin], area between the C-peptide baseline and the C-peptide suppression curve [AOCc], absolute maximal difference from baseline [Sdiff] and glucose clamp measurements. The glucose clamp measurements included maximum infusion rates (Rmax) and time to Rmax (TRmax) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h (40Gtot) and total glucose infused (Gtot) during the study. RESULTS For the pharmacokinetic assessment, statistically greater values of insulin Cmax and β were found for the 50/50 mixture, whereas the 70/30 mixture had a greater MRT. Statistical differences were also detected in glucodynamics, with greater values of Rmax and (40Gtot) found with the 50/50 mixture. Notably, differences were not detected for insulin AUCx0 and Gtot values. CONCLUSIONS Higher insulin concentrations and a greater initial response were present with the 50/50 mixture, but the two mixtures had equivalent bioavailability and cumulative effects. These results support use of the 50/50 mixture in situations where greater initial glucose control is required.

Relating Glucose Clamp Profiles to Reduction of Blood Glucose After Insulin Administration

A model was established allowing prediction of blood glucose response from glucose clamp results performed in healthy volunteers. Data from published studies performed in healthy volunteers were used to establish, test, and validate a model for the evaluation of glucose reductions from glucose clamp results. Studies included those that measured blood glucose and glucodynamic response over time after administration of 0.05 U/kg of regular human insulin (HR) and insulin lispro (LP) with and without the benefit of a glucose clamp procedure. An inhibitory effect E(max) model was used to describe the relationship; the model differed between the HR and LP responses by the intensity of the counterregulatory response as assessed by glucagon measurements. The relationships were used to predict blood glucose responses from a clamp study assessing NPH insulin and HR administrations. Glucose concentrations measured after administration of NPH insulin and HR without a clamp were compared to the model-predicted results to assess the accuracy of the model predictions. The E(max) model successfully correlated the glucose clamp results with the blood glucose depressions in the presence and absence of a counterregulatory response. However, predictions of glucose depression were only accurately modeled in the absence of a counterregulatory glucagon response. The correlations established with a minimal counterregulatory response underscore the value of glucose clamp procedures in defining the time-activity profiles of insulins when the clamp is established at fasting glucose concentrations.