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Pharmacokinetic/Pharmacodynamic Modeling of Glucose Clamp Effects of Inhaled and Subcutaneous Insulin in Healthy Volunteers and Diabetic Patients

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Pharmacokinetic/Pharmacodynamic Modeling of Glucose Clamp Effects of Inhaled and Subcutaneous Insulin in Healthy Volunteers and Diabetic Patients Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE Received; February 12, 2010 Published online; September 29, 2010 Accepted; June 15, 2010 doi; 10.2133/dmpk.DMPK-10-RG-017 1 Pharmacokinetic/pharmacodynamic modeling of glucose clamp effects of inhaled and subcutaneous insulin in healthy volunteers and diabetic patients Cornelia B. Landersdorfer1,2 and William J. Jusko1 1Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA 2Ordway Research Institute, Albany, NY, USA Support: This work was supported by the UB-Pfizer Strategic Alliance. Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 2 Running title: PK/PD of Inhaled Insulin Address of correspondence: William J. Jusko, PhD, Department of Pharmaceutical Sciences, University at Buffalo State University of New York, 565 Hochstetter Hall Buffalo, NY 14260, USA. Phone: (716) 645-2855 x225 Fax: (716) 645-3693 E-mail: [email protected] Number of text pages: 28 Number of tables: 2 Number of figures: 3 Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 3 Abstract The pharmacokinetics and pharmacodynamics (PK/PD) of inhaled insulin in humans have not been modeled previously. We rationalized a model for the effects of inhaled insulin on glucose infusion rate during a euglycemic clamp study based on the mechanism of insulin action and compared parameter estimates between subcutaneous and inhaled insulin in healthy and diabetic subjects. Published data from two studies in 11 healthy volunteers and 18 type 1 diabetes patients were digitized. The subjects received four different doses of inhaled insulin and one or three different doses subcutaneously at the start of a 10 h glucose clamp. All data were modeled simultaneously using NONMEM VI. Insulin pharmacokinetics were described by a one-compartment model with one (inhaled) or two (sc insulin) first-order absorption processes and first-order elimination. Insulin effects on glucose were described by an indirect response model. A biophase direct effect equation for the glucose infusion rate was implemented. Pharmacodynamic parameter estimates were 15.1 mg/min/kg for maximal glucose infusion rate (GIRmax) and 88.0 mIU/L for SC50 for diabetic and 62.9 mIU/L for healthy subjects. A PK/PD model based on fundamental principles of insulin action and glucose turnover suggests comparable potencies of inhaled and subcutaneous. Keywords: Diabetes, insulin sensitivity, mechanism-based modeling, pharmacokinetics, pharmacodynamics Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 4 Introduction The number of diabetic patients is increasing and efforts are being made to improve therapy and develop new therapeutical approaches. Timely diagnosis and adequate treatment are vital for prevention or delay of long-term complications. Type 2 diabetic patients suffer from both insulin resistance and β-cell failure [1]. Type 1 diabetes is mainly characterized by β-cell failure, however insulin resistance also plays a role [2]. Numerous different diagnostic tests are available for clinical use to evaluate β-cell function [3] and insulin sensitivity [4]. The hyperinsulinemic euglycemic glucose clamp technique, originally developed by DeFronzo et al. [5], is considered one of the gold standard methods to measure insulin sensitivity and used as reference for other methods [6, 7]. Generally, a constant rate insulin infusion is given which results in insulin concentrations higher than the physiological baseline. Blood glucose is measured frequently and maintained within the euglycemic range by glucose infusions with variable rates. As hepatic glucose production is assumed to be completely inhibited by the exogenous insulin infusion, glucose infusion rate (GIR) equals glucose utilization rate. Effects of exogenous insulin are often measured by comparing the areas under the GIR vs. time curve after various doses of insulin [8, 9]. With this approach, the doses in a study can be compared but effects of other doses or modes of administration cannot be accounted for and the underlying mechanism cannot be described. Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 5 Timely initiation of insulin therapy is often the best way to improve glucose control in diabetic patients. Due to anxiety and resistance of patients towards injecting insulin, they frequently remain on therapy with oral antidiabetics although satisfactory blood glucose control may not be achieved [10]. To overcome this barrier, various formulations of inhaled insulin including powder and liquid aerosol inhalers were and are being developed by several companies. In a systematic literature review, inhaled insulin was found to be as effective clinically as injected short-acting insulin with a slightly faster onset of action and was preferred by most patients [11]. However costs are considerably higher with the inhaled formulation [11]. A patient preference study in 344 Type 1 and 2 diabetic patients in the UK reported that 63 to 81% of the patients preferred inhaled over injected insulin [12]. Most recently, a two-year safety and efficacy study in type 2 diabetic (T2DM) patients found a small nonprogressive decrease in forced expiratory volume, similar improvement in HbA1c, lower fasting plasma glucose and lower weight gain with inhaled versus sc insulin [13]. Comparable efficacy and lung function were reported in pediatric T1DM patients who received inhaled or sc insulin for three months [14]. In general, similar safety and efficacy of inhaled and sc insulin, despite small changes in lung function was concluded [15]. The effect of spray instilled insulin in rats was modeled previously [16], however the effect of inhaled insulin in human healthy volunteers and diabetic patients has not been modeled. Therefore we sought to 1) rationalize a PK/PD model for the effects of inhaled insulin on glucose infusion rate during a Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 6 euglycemic clamp study based on the mechanism of insulin action, 2) apply this model to literature data from glucose clamp studies to provide an example, and 3) compare the parameter estimates between subcutaneous (sc) and inhaled insulin in healthy volunteers and diabetic patients. Methods Data. Published data from two crossover studies [8, 9] were digitized (Graph-to- Digital Data Converter: Graph Digitizer®, Version 2.0, http://www.geocities.com/graphdigitizer/.htm). Both studies reported average insulin concentrations and GIR for each dose and route of administration and had frequent sampling times; individual subject data were not available. In both studies regular human insulin was utilized. The study by Brunner et al. [9] included 18 type 1 diabetic (T1DM) patients who were C-peptide negative and were on intensive insulin therapy. After an overnight fast, the patients received a variable insulin infusion over 5 h to achieve stable euglycemia (about 7.2, range 5.0-9.4 mmol/L). For inhaled insulin, the insulin infusion was stopped at the time of the dose and for sc insulin at 10 min after the sc dose. The patients received single doses of 0.3, 0.6, 1.2, and 1.8 IU of human regular insulin per kg body weight by inhalation and 0.12 IU / kg sc. Inhaled insulin was administered by a liquid aerosol device (AERx iDMS). Sc insulin was administered by Actrapid HM Penfill 100 U/mL (Novo Nordisk, A/S). After insulin administration the patients underwent a 10 h glucose clamp study during which glucose concentrations were held constant at 7.2 mmol/L. The mean (standard Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 7 deviation) weight of the patients was 72.6 (8.8) kg, age was 35.4 (5.9) years, and HbA1c (glycosylated hemoglobin) was 8.1 (0.9) %. Rave et al. [8] administered doses of 60, 90, 120, and 150 IU of inhaled insulin to each of 11 healthy volunteers (HV) in a crossover fashion. Human insulin was delivered by a dry powder inhaler (SPIROS® blisterdisk inhaler, 11% micronized insulin crystals with carrier monohydrate NF, median particle size was 2-3 μm for insulin and 150 μm for lactose). In addition each healthy volunteer received two out of three doses of sc regular human insulin: 8, 14, or 20 IU (Humulin® R) which was administered by syringe. Doses were given after an overnight fast. For 10 h after insulin administration, blood glucose was clamped at 5% below the individual mean baseline which was determined by measurement before insulin administration. The Biostator glucose-controlled insulin infusion system (GCIIS, Life Science Instruments, Elkhart, USA) was utilized to regulate glucose infusion rates in response to the changes of blood glucose levels. The healthy volunteers (eight female, five male) were between ages of 22 and 42 and required to have a BMI of ≤ 27 kg/m2. Pharmacokinetics. For modeling the insulin concentrations, models with one and two disposition compartments, with and without an absorption lag-time, and with first-order, zero-order, mixed-order (Michaelis-Menten), parallel first-order and zero-order, first-order and mixed-order, two parallel first-order absorption compartments, sequential zero-order and first-order or first-order and first-order Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE 8 absorption were tested. For the modeling, the doses for T1DM patients were converted from IU/kg to IU by use of the reported average weight of 72.6 kg. The final PK model is depicted in Figure 1. Inhaled insulin PK in both T1DM and HV was described as: dI Lung k I (1) dt a_Inh Lung dIs ILung CLT ka_Inh Is (2) dt V V where ILung is the amount of insulin at the absorption site in the lung, ka_Inh is the first-order absorption rate constant, Is is insulin plasma concentration, CLT is apparent clearance assuming the bioavailability of the sc dose is 100%, and V is apparent volume of distribution. The initial condition for ILung is 0. The initial condition of Is is Is(0) which was estimated.
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