Personalizing Drug Delivery

Transcription

1 Personalizing Drug Delivery Emilio Perucca, M.D, Ph.D. Clinical Pharmacology unit, University of Pavia & C. Mondino National Neurological Institute, Pavia, Italy Washington, December 7, American Epilepsy Society Annual Meeting

2 Disclosure Name of Commercial Interest Type of Financial Relationship Eisai, GSK, Viropharm GSK, Lundbeck & Viropharma Speakers fee Advisory board 2 American Epilepsy Society 2013 Annual Meeting

3 Learning Objectives Develop rational criteria to personalize choice of delivery systems, routes of administration and dosing regimens Acquire familiarity with advantages, limitations and indications of unusual ways of delivering anti-seizure medications 3 American Epilepsy Society 2013 Annual Meeting

4 Personalizing Treatment is More than Deciding What to Give: Tusko s Story On August 3, 1962, the prize of Oklahoma City Zoo" was injected with LSD using a mg kg 1 dose previously used in cats Within 5 min, Tusko trumpeted, collapsed, fell heavily onto his right side.. and went into status epilepticus Despite several unsuccessful attempts to control the seizures, about one hour later Tusko was dead. West et al. Science 1962;138:

5 Personalising Treatment is More Than Deciding How Much To Give Which is the best formulation or delivery system for the individual patient or situation? How should the dose be divided? Which is the most appropriate route of delivery? 5

6 Serum AED Concentration Personalizing Formulation: Flatter Is Better? Serum AED Concentration Profiles at Steady-State vs Risk of Toxicity or Seizure Breakthrough Narrow Therapeutic Index Drug Immediate-release formulation (b.i.d.) Controlled-release formulation (o.i.d) Threshold concentration for toxicity Minimum concentration required for seizure control 6 8 AM 2 PM 8 PM 2 AM 8 AM

7 AEDs for which Sustained-Release Formulations are Currently Available in the U.S. Carbamazepine Divalproex sodium Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Topiramate 7

8 Percentage of patients Seizures / month (mean) Percentage of patientis Double-Blind Randomized Trial of Controlled Release (CR) vs Immediate-Release (IR) Carbamazepine Cross-over trial in 48 patients with seizures or intermittent side effects Physicians asked to optimize dose while trying to minimize dosing frequency Dose optimization followed by 1-month evaluation Patients with Monthly Patients intermittent side seizure requiring 3 or 4 effects (%) frequency daily doses (%) P< % 54% 10 5 P= P= % 19% CR IR CR IR CR IR Canger et al, Acta Neurol Scand 1990;82:9-13

9 What Difference Can a Formulation Make? Comparison of Two Double-Blind Trials of Carbamazepine in the Elderly % of patients retained on treatment 80 Brodie et al., % N = 102 Lamotrigine Regular CBZ 42% N = Brodie et al, Epilepsy Res. 1999;37:81-7;

10 What Difference Can a Formulation Make? Comparison of Two Double-Blind Trials of Carbamazepine in the Elderly % of patients retained on treatment 80 Brodie et al., 1999 Saetre et al, % N = 102 Lamotrigine Regular CBZ 73% N = 93 67% N = 91 Lamotrigine CBZ controlledrelease 40 42% 30 N = Dosing and titration schemes were identical in both trials. Trial duration was longer in Saetre s trial (40 vs 20 weeks) Brodie et al, Epilepsy Res. 1999;37:81-7; Saetre et al, Epilepsia 2007;48:

11 Extended-Release Formulations: Potential Advantages and Concerns Advantages Concerns Lesser fluctuation in serum drug levels Most valuable for patients susceptible to peak concentrationrelated side effects Lack of comparative data with the IR formulation are there advantages, and if so for whom? Any risks with switching? Benefits in convenience, and possibly in compliance Shorter forgiveness period? Cost-effectiveness? 11 IR = immediate-release

12 Serum AED Concentration Is Flatter Always Better? Serum AED Concentration Profiles at Steady-State vs Risk of Toxicity or Seizure Breakthrough Wide Therapeutic Index Drug Immediate-release formulation (b.i.d.) Threshold concentration for toxicity Controlled-release formulation (o.i.d) Minimum concentration required for seizure control 12 8 AM 2 PM 8 PM 2 AM 8 AM

13 Percentage Distribution of Seizures Over 24-hour Periods in 41 Consecutive Children with Frontal Lobe Seizures 8 pm 8 am 8 pm 8 am 8 pm 13 Ramgopal et al., Curr Neurol Neurosci Rep 2013; 13:339 - modified based on further information kindly provided by Dr. T. Loddenkemper

14 Number of seizures Distribution of Frontal and Temporal Lobe Seizures vs Time of the Day from a Study of 44 Adults and Children Frontal lobe seizures (n=31) Temporal lobe seizures (n=71) Time of day 14 Pavlova et al, Neurology 2012:78:

15 Higher Evening AED Dose for Nocturnal and Early Morning Seizures Retrospective analysis of 17 children with uncontrolled nocturnal or early morning seizures All children were switched to a proportionally higher evening AED dose without changing the total daily dose After a mean follow-up of 5.3 months, 11 became seizure-free and 4 had 75-90% reduction in their seizures Guilhoto et al, Epilepsy Behav 2011;20:

16 Personalising Route of AED Delivery Special Situations Inability to take solid dosage forms (e.g., infants, young children) Malabsorption syndromes Inability to take oral medications Need for emergency treatment 16

17 Percentage of patients Superiority of i.m. Midazolam (MDZ) over i.v. Lorazepam (LRZ) for Prehospital Treatment of Status Epilepticus 80 Success Rate* 73.4% 60 n= % n=445 p < *Primary endpoint (% arriving to ER free from seizures without rescue therapy) 0 i.m. MDZ i.v LRZ Intramuscular midazolan is not FDA-approved for prehospital treatment of status epilepticus 17 Silbergleit et al, New Engl J Med 2012; 366:

18 Plasma Diazepam (ng/ml) Diazepam: Speed of Rectal Absorption in Infants n=8 n=9 n=10 Solution, 0.7 mg/kg n=9 n= n=5 n=10 n=8 Suppository, 5mg n=5 n=9 n=8 Efficacious levels Time (min) n=10 Knudsen FU, Acta Ped Scand 1977;66:563-7

19 Rapid Onset of Action of Rectal Diazepam in Preventing Seizure Recurrence in Children with Acute Repetitive Seizures (n=133) p = Kriel et al, Pediatr Neurol 1999;20:282-8

20 Is the Rectal Route Feasible for Short-Term Substitution in AED Therapy? Feasibility demonstrated Carbamazepine Lamotrigine Levetiracetam Phenobarbital Topiramate Feasibility questioned Felbamate Gabapentin Oxcarbazepine Phenytoin Valproic acid Anderson and Saneto, Adv Drug Deliv Rev 2012;64:

21 Success rate (%) Success Rates* in 3 Double-Blind Trials of Buccal Midazolam (MDZ) vs Rectal Diazepam (DZP) in Children with Convulsions McIntyre 1 (n=219) Scott 2 (n=24) Mpimbaza 3 P<0.001 NS 56% 59% 27% 75% Children with malaria (n=222) 64% NS 68% Children without malaria (n=108) P= % 74% 21 0 DZP MDZ DZP MDZ DZP MDZ DZP MDZ 0.5 mg/kg 0.5 mg/kg 10 mg 10 mg 0.5 mg/kg 0.5 mg/kg 0.5 mg/kg 0.5 mg/kg *Cessation of seizures within 10 min (without recurrence in 1 h for studies 1 and 3) Buccal midazolam is not FDA-approved for treatment of convulsions 1 MacIntyre et al, Lancet 2005;366:205-10; Scott et al, Lancet 1999,353:623-6; 3 Mpimbaza et al,pediatrics 2008;121:e58-64

22 Seizure cessation in 5 min (%) Randomized Trial of Buccal Midazolam vs Intravenous Diazepam in 122 Children with Convulsions Time to seizure control after dosing (minutes) Time to seizure control after decision to treat (minures) Seizure cessation (%) Time to effect Time to effect after after dosing (min) decision to treat (min) NS 93% 85% P= P= DZP MDZ DZP MDZ DZP MDZ 22 Dose was 0.3 mg/kg for i.v diazepam and 0.3 mg/kg for buccal midazolam Buccal midazolam is not FDA-approved for treatment of convulsions Talukdar & Chakrabarty, Brain Dev 2009; 31:744-9

23 Seizure cessation in 5 min (%) Randomized Trial of Sublingual Lorazepam vs Rectal Diazepam in 436 Children with Convulsions Seizute cessation in 10 min (%) Seizure cessation in 20 min (after a second dose at 10 min)(%) Seizure cessation Seizure cessation in Seizure cessation in 5 min (%) 10 min (%) (primary endpoint) in 20 min (%) P=0.022 P= P= % 79% 83% 38% 28% % DZP LRZ DZP LRZ DZP LRZ Dose was 0.5 mg/kg for rectal diazepam and 0.1 mg/kg for sublingual lorazepam Buccal midazolam and sublingual lorazepam are not FDA-approved for treatment of convulsions 23 Malu CK et al., J Child Neurol 2013; July 31 pub ahead of print)

24 A Shortcut from the Nose to the Brain: Intranasal Delivery Bypasses blood brain barrier and first-pass effect Easily applicable in convulsing or non-collaborative patients Only feasible for potent AEDs (<20 mg/dose) Absorption generally better for lipophilic drugs. Solubilization issues with some agents Concerns with inter-subject variability, impact of nasal pathology and local irritation Evidence of anti-seizure effectiveness best provided for midazolam and lorazepam 24 Misra and Kher, Curr Pharm Biotech 2012;13:

25 Seizure cessation in 5 min (%) Time to seizure control after dosing (minutes) Time to seizure control after arrival to ER (minures) Randomized Trial of Intranasal Midazolam vs Intravenous Diazepam for Acute Childhood Seizures (n=50) Seizure cessation (%) Time to effect Time to effect after after dosing (min) arrival to ER (min) NS P=0.05 P= % 67% DZP MDZ DZP MDZ DZP MDZ All children had been convulsing for >10min at time of enrolment. Dose was 0.3 mg/kg for i.v diazepam and 0.2 mg/kg for intranasal midazolam Intranasal midazolam is not FDA-approved for treatment of convulsions 25 Thakker & Shanbag, J Neurol 2013; 260:470-4

26 Factors to be Considered in Personalizing Emergency Treatment in a Convulsing Child Setting (hospital vs pre-hospital household vs ambulance) Ease of access to an i.v. line Availability and regulatory status of specific medications / formulations Appropriateness of providing rescue medication (history of prolonged seizures and seizure clusters, skills and collaboration of family members, distance from nearest hospital, etc.) Perceived risk/benefit ratio of different treatment options (or no treatment) in the child Cost and affordability 26

27 Innovative Delivery Systems for Personalized AED Therapy in the Future Novel formulations (microspheres, microemulsions, liposomes, proliposomes, nanoparticles, exosomes, ethosomes, dendrimers) including multifunctionalized nanoparticles targeting specific brain sites Intracerebroventricular, convection-enhanced and polymeric brain delivery systems Imaging-guided brain drug delivery Conditional response devices, e.g. drug delivery systems triggered by epileptic activity or changes in brain state preceeding seizure onset Pehlivan, Brain Res, 2013; doi /s ; Braccioli et al, Mol Neurobiol, 2013: doi /s ; Barua et al, J Neurosci Methods. 2013;220:1-8. Ding et al, Drug Discovery Today 2013 doi /j.drudis

28 Targeted Drug Delivery at the Site of the Epileptic Focus: The Subdural Hybrid Neuroprosthesis The subdural hybrid neuroprosthesis is not FDA-approved for treatment of seizures 28 Ludwig et al, Epilepsy Res. Treat. 2010; doi: /2010/725696

29 Implantable Convection-Enhanced Catheter System for Chronic Intermittent Drug Delivery to the Brain 29 Barua et al, J Neurosci Methods. 2013;220:1-8

30 Conclusions Efficacy and tolerability of an AED depend on modality of delivery formulation, dosing scheme and route Delivery needs to personalised based on the clinical situation and the individual s characteristics Innovative ways of delivering AEDs could lead to therapeutic breakthroughs in the future 30