Karam Alali (1), Orwa Albitar (1,9), Siti Fatimah Ismail (3), Kamarul Aryffin Baharuddin (3), Sanihah Abdul Halim (4), Wan Mohd Izani Wan Mohamed (4), Chee Toong Chow (5), Neoh Kar Keong (6), Tuan Salwani Tuan Ismail (7), Farisyah Syakirah Mohd Zain (8), Mohd Jamsani Mat Salleh (8), Irene Looi (2), Purnima Devi Suppiah (2), Siti Maisharah Sheikh Ghadzi (1), Sabariah Noor Harun (1).
(1) Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11700 Penang, (2) Clinical Research Center, Hospital Seberang Jaya, 13700 Penang, Ministry of Health Malaysia, (3) Department of Emergency Medicine, School of Medical Sciences, Universiti Sains Malaysia, 15200 Kota Bharu, Malaysia, (4) Department of Internal Medicine, School of Medical Sciences, Universiti Sains Malaysia, 15200 Kota Bharu, Malaysia, (5) Department of Emergency & Trauma, Hospital Seberang Jaya, 13700 Penang, (6) Medical Department, Kek Lok Si Charitable Hospital, 11500 Penang, (7) Endocrinology Unit, Hospital Universiti Sains Malaysia, 16150 Kota Bharu, Malaysia, (8) Pathology Department, Hospital Seberang Jaya, 13700 Penang, (9) Roche Pharma Research and Early Development, 4070 Basel, Switzerland.
Introduction/Objectives: Regardless of pre-stroke diabetes status, patients admitted to the hospital for acute ischemic stroke (AIS) are frequently observed to have hyperglycemia [1]. Hyperglycemia is associated with poor stroke outcomes [2] and insulin therapy to achieve normoglycemia during the acute phase is associated with better clinical outcomes in other groups of critically ill patients [3]. In contrast, no conclusive evidence exists that normalizing serum glucose during the acute phase of ischemic stroke improves outcomes [1]. Not stratifying patients according to their pre-stroke glycemic status[4] and differential pathophysiology of insulin regulation in both pre-stroke diabetic and non-diabetic patients during the acute phase [5] are proposed mechanisms to explain the inability to demonstrate expected benefit. The two groups had similar degrees of hyperglycemia but very different clinical outcomes [6]. In general, hyperglycemia in diabetic patients is secondary to a relative deficiency of insulin, whereas, in non-diabetic patients, it was suggested that they are not in a hypo-insulinemic state. Still, instead, hyperglycemia is part of the systemic stress response [7]. Thus, these may affect insulin pharmacokinetics, requiring different approaches to treating hyperglycemia in those groups. By understanding the differences between the pharmacokinetic behaviors of administrated insulin during AIS hyperglycemia in both populations, an appropriate clinical decision could be made to improve the treatment plan and, therefore, improve stroke outcomes. Thus, we aimed to develop a pharmacokinetic model of regular SC insulin (Actrapid) therapy for hyperglycemia during acute ischemic stroke among stroke patients with and without pre-existing diabetes.
Methods: This prospective study was conducted in two-stroke centers in Malaysia. AIS patients with or without pre-existing diabetes who developed hyperglycemia within 72 hours of admission treated with SC insulin were recruited. Pre-existing diabetes status was confirmed by A1C level ≥ 6.5%. At least three blood samples were collected sparsely at 0, 0.5, 1.5, 3, 4, 6, and 8 hours of the SC insulin therapy. The PopPK model of the regular SC insulin was developed in both populations. One and two-compartment models with additive, exponential, and combined additive and exponential error models and lag absorption models were investigated, and potential covariates were added to improve the maximum likelihood estimation, goodness-of-fit plots, and visual predictive checks. Sampling importance resampling (SIR) was used to estimate the parameter uncertainty. NONMEM v.7.4 and PsN v.5.3.1 were used.
Results: Fifty-three AIS diabetic patients (DM) and twenty-nine nondiabetic patients (non-DM) were included. A one-compartment model with first-order absorption and elimination was selected for both populations. A combined additive and exponential error model for the DM model and an exponential error model for the non-DM model were selected. Final PopPK parameters for the DM model were: Absorption rate (Ka)=1.22 h-1, apparent clearance (CL/F)=26.7 L/h, apparent volume of distribution (V/F)=247 L, rate of unknown dosing history (R1)=0.15 h-1, endogenous insulin concentration (EIC)=6.25 µIU/mL, additive error=8.54 µIU/mL and proportional error=22.8% while in the non-DM model: Ka=3.92 h-1, CL/F=25.8 L/h, V/F=76.3 L, R1=0.57 h-1, EIC=13.8 µIU/mL, proportional error=72.4%. Inter-individual variability (IIV) was below 100% for Ka, V/F, and Cl/F in the DM model, while it was below 200% for V/F in the non-DM model. Relative standard errors (RSEs) were precisely estimated below 30% for all parameters and IIVs in both models. DM patients’ absorption rate increased by 32% every five years after 60 (Kapop=(Age/60)5.97). The clearance decreased exponentially by approximately 10% for each 1kg/m2 increase in the body mass index (BMI) after 25.6 kg/m2 (CLpop=e-0.128*(BMI-25.6)) and for each 0.5 mmol/l increase in urea concentration above 5.3 mmol/l during the acute state (CLpop=e-0.207*(Urea-5.3)). Non-DM patients with modified Rankin Score (MRS)>2 showed a six-time increase in regular SC insulin clearance compared to patients with MRS≤2.
Conclusions: Regular SC insulin dose adjustment is needed in diabetic and nondiabetic patients during AIS. Dose reduction is necessary for AIS diabetic patients above 60, with a BMI above 25.6 kg/m2, or having an urea level above 5.3 mmol. At the same time, the dose should be increased for nondiabetic patients with MRS>2.
References:
[1] Johnston, K.C., et al., Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial. JAMA, 2019. 322(4): p. 326-335.]
[2] Tsivgoulis, G., et al., Association of Baseline Hyperglycemia With Outcomes of Patients With and Without Diabetes With Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Propensity Score-Matched Analysis From the SITS-ISTR Registry. Diabetes, 2019. 68(9): p. 1861-1869.
[3] Krinsley, J.S., et al., Continuous glucose monitoring in the ICU: clinical considerations and consensus. Crit Care, 2017. 21(1): p. 197.
[4] Long, M.T., D.B. Coursin, and J.S. Krinsley, Treatment of Hyperglycemia in Patients With Acute Stroke. Jama, 2019. 322(22): p. 2248.
[5] Reshi, R., et al., Hyperglycemia in acute ischemic stroke: Is it time to re-evaluate our understanding? Med Hypotheses, 2017. 107: p. 78-80.
[6] Zhu, B., et al., Stress Hyperglycemia and Outcome of Non-diabetic Patients After Acute Ischemic Stroke. Frontiers in Neurology, 2019. 10.
[7] Tziomalos, K., et al., Stress hyperglycemia and acute ischemic stroke in-hospital outcome. Metabolism, 2017. 67: p. 99-105.
Reference: PAGE 32 (2024) Abstr 11203 [www.page-meeting.org/?abstract=11203]
Poster: Drug/Disease Modelling - Other Topics