Determination of toxic (harmful) dose in children: an industry approach Soraya Madani, PhD Exploratory Clinical Development Novartis Pharmaceuticals ANEC Konferenz Kindersichere Verpackungen Conference on 23 Sept 04 Packaging of Medicines and the Safety of Children

Background  Child resistant packaging mandatory in US to fullfill requirements of the Poison Prevention Packaging Act 1970 and amended 1995 to include ‘senior-friendly’ packaging  Similar regulation are discussed in the EU  Legislation application: certain house hold substances, and oral prescription drug products  Legislation aim: prevent children from serious injury or illness as a result of handling or accidental ingestion of drugs

 Failure definition (according to CFR title 16, part 1700) for solid oral drugs packed in unit dose packs: any child of 11.4 kg* who opens or gains access to the number of individual units which constitute the “harmful dose”, or a child who opens or gains access to more than 8 individual units  The CFR title 16, part 1700 discusses packaging test procedures extensively. But it is not precized how the harmful dose should be established * based on CDC growth chart an 11.4 kg child: manily yr (2 year-old 50 th percentile)

 Harmful dose should be the lowest dose that may cause toxicity. However, this is rarely known in practice. What is more generally determined and is used as a basis is the MTD (maximum Tolerated Dose) in adults  MTD: the largest dose of a drug a patient can take without unacceptable adverse side effects  In Drug Development: usually the top dose in the single-dose escalation human safety-tolerability trail that does not cause unacceptable acute serious adverse event

 Often have information about maximum tested dose in humans, but lack maximum tolerated dose (MTD)  Lack paediatric information (unless target population is children)  Degree of child resistance is linked with toxicity of the drug (the lower the unit #s the more difficult to access the pharmaceutical) Is lower # of units necessarily safer?  Compliance may decrease  not safe  Bypassing the packaging  increase possibility of accidental ingestion General challenges

Harmful (toxic) dose evaluation Examples

 Limited human information: Drug A  Some human information: Drug B  Information rich: Drug C  The toxicity of concern is acute (single dose) toxicity, not chronic toxicity  The single dose data from single dose escalation. The top dose is considered MTD.  The nature of toxicity is similar in adults and children Assumptions for the harmful dose determination? Examples

Drug A: Lack of comparable human systemic exposure as a reference  Stage of development: Phase 2  Route of administration: inhalation, with capsule inhaler  Drug product packed looks like oral solid dosage forms: capsules and blisters  Particular challenge: accidental ingestion  oral vs. human exposure information via inhalation  In healthy volunteers: SD escalation (inhaled) up to 2000 μg (no SAE observed)  MTD: N/A. Therapeutic dose: not known (400 μg or 800 μg) in form of 400 μg capsules  Pediatric data: N/A  Animal Toxicology : NOAEL (Not Observed Adverse Event Level) in two species rat and dog

Drug A: calculation  Safety margin approach applied: NOAEL from animal toxicology used as the reference  Normally, uncertainty factors for interspecies (10x) and intraspecies (x10) differences are taken into account in risk assessment of xenobiotics  Safety margin of ≥10-fold criteria Safety margin = AUC NOAEL / AUC human  AUC comparison not preferred, Toxicokinetics via oral but human PK via inhalation Safety margin = NOAEL (mg/m 2 ) / Dose child (mg/m 2 )  Dose comparison was preferred (mg/m 2 ). Using the NOAEL dose in most sensitive species (ref) and 0.4, 2 and 4mg accidental ingestion in a child (1, 5 and 10 capsules of 400 μg) as the comparator (conversion factor is 23 for a child and 37 for an adult)  Safety margins were: 200x, 45x, 23x respectively

Scaling: adult to children BWT vs. BSA Body Weight (BWT) approach: Child dose = Adult dose (mg/kg) * /child WT (11.4 kg) Body surface area (BSA) approach : Rowland and Tozer  The SA of a child can be determined from its BWT using the observation that SA is proportional to BW to the 0.7 power (this is shown in humans). Hence the below mathematical relationship exists: Child dose = 1.4 ** x (Child WT/70 kg) 0.7 x adult dose 1 Assume 70 kg adult ** conversion factor 1 Rowland and Tozer Clinical Pharmacokinetics.3 rd Edition. Lippinot Williams & Wilkins

Scaling: BWT vs. BSA from systemic exposure (PK) perspective Body Weight (BWT) approach:  predicting drug clearance (CL) using per kg model will underestimate clearance, error increases as the WT decreases (e.g 10% for a 47kg, but 200% for 3.4 kg new born) 1  Simple, Commonly used, produces the most conservative estimate, results in the lowest unit #s in the blister package  compliance, bypassing the packaging  Safer?! Body surface area (BSA) approach :  Predicting CL based SA model gives a better prediction but leads to an over prediction of about 10% at BWT < 20 kg  Research shows that dosage regimen, cardiac output and renal blood flow as well as GFR (Glomerular Filtration Rate) in children and adults of different sizes correlate better with BSA than BWT  Because CL relates dose to systemic exposure (AUC) and the physiological factors above are related to CL, using SA as a method of calculation has its justification 1 Anderson et al., (1997) Clinical PK 33 (5). Pharmacokinetics of ingested xenobiotics in children: A comparison with adults. De Zwart et al, RIVM report /2002

Drug B: sub-MTD in adults  Stage of development: 2b  SD escalation in HV (healthy Volunteers): up to 40 mg  MTD: N/A. At 40 mg observed mild AE (Adverse Event, but no SAE (Serious Adverse Events) was observed.  Therapeutic dose: Not Available N/A. 1.25, 2.5 and 5 mg are the possibilities  Pre-clinical information in animal species: NOAEL (Not Observed Adverse Event Level) was not defined under acute oral conditions. 100 mg/kg was well tolerated.  Pediatric data: (N/A)

Drug B: calculation  Only human data utilized. 40 mg was assumed as the MTD and the reference  Two scaling approaches were considered: BWT Body Weight) and BSA (Body Surface Area) normalization  BWT: MTD (mg/kg)/11.4 kg = 7 mg  1 tablet/ blister  BSA*: Child dose = 1.6 x (Child WT/70 kg) 0.7 x adult dose = 18 mg  3 tablet/blister  Final decision pending after pediatric data available *Rowland and Tozer Formula (Clinical Pharmacokinetics text book). 1.6 is the conversion factor for a 11.4 kg child

Drug C: information rich!  Stage of development: Marketed. New formulation development  Therapeutic dose : 250-mg qd (125 mg and 250-mg tablets)  Single dose escalation safety-tolerability trial in HV: up to mg qd (No SAE observed)  MTD: not reached in human subjects, below-MTD: 1500-mg  Clinical studies up to 2000 mg had similar AE as the 250 and 500 mg  Data in children: available  Post-marketing reports of acute overdose: available  Tox data: both short and long term studies available

Toxicology estimation  Acute oral studies (SD)  in rat and mice  lethal dose > 4000 mg/kg  in monkey  well tolerated up to 300 mg/kg  Chronic dosing (26 wk):  No marked toxic effects in rats or monkey  up to 300 mg/kg  Juvenile rats similar exposure to adults studied up to 100 mg/kg  Safety margin  10-fold : NOAEL (not observed adverse event level) in most sensitive species as the reference  The harmful dose would be 1100 mg

PK estimation: children and adults  N= 36, ages 4-12 years, sparse sampling, steady state data  Doses based on WT < 20 kg (62.5 mg), kg (125 mg)  Population PK (popPK) applied  BWT a covariate influencing the CL/f of the drug (CL/F = (BWT – 43.6))  CL/f in a child of 11.4 kg is about 16.4 L/h compared to 26 L/h in a 70 kg adult (~ 30% lower)  If to only use human PK data: using the AUC from maximum SD trail in adults as reference (1500 mg) and the above mathematical relationship  Harmful dose : 760 mg (below harmful dose)

Post-marketing reports of dug overdose in children ≤ 18 y  4/9 cases were children < 6 years of age.  Overdose ranged from mg  All but one case were asymptomatic  in the case of a 5-year old female that displayed ataxia and abnormal coordination after ingestion of 700 mg of Drug C by accident  At 700 mg the symptoms abated within six hours  If to use post marketing data: harmful dose 700mg mg

Drug C: Summary  Preclinical tox: lethal dose is 4000 mg/kg. Absence of acute or chronic toxicity at 100 mg/kg (NOAEL) in most sensitive animal species  1100 mg (none toxic dose)  Clinical PK in adult and children: CL/f in a child of 11.4 kg is 30% lower. Using SD adult AUC at 1500 mg (maximum tested dose) as reference  750 mg (none toxic dose)  Clinical experience: Wide margin of safety based on the clinical experience (up to 2000 mg chronic dosing)  Lack of SAE upon accidental ingestion of up to 2000 mg in children 750 mg was determined as sub-harmful dose in children of 11.4 kg  blister packaging of 3 or 6 units based on the dosage strength

Drug C In the absence of the wealth of the data:  simple Body weight (mg/kg) scaling approach:  Maximum tested dose from the SD escalation study in adults= 1500 mg MTD (mg/kg) = 1500/70= 21 mg/kg 21 mg/kg x 11.4 = 244 mg  244 mg is a value below therapeutic dose! and 3-fold lower than 750 mg

Lessons learned for determination of toxic dose  A single method can not be applied for all drugs  Consider whether compound has special developmental toxicity (e.g. bone metabolism, cognitive functions). Consider juvenile Tox and Reprotox data if available, and relevance for acute dosing  If no specific toxicity, scale the single dose adult MTD down to a 11.4 kg child (based on BW, BSA, or more sophisticated approaches (e.g., PK- PD)).  Use lower dose if specific toxicity is expected, or higher dose if side effects are benign.  If paediatric data are available, consider tolerability and PK results to refine scaling.  Where applicable, integrated approach. If possible, Include data from: clinical, human PK, animal PK and toxicology

Proposed decision tree for determination of harmful (toxic) dose Maximum tolerated dose (MTD) in adults (oral) BSA 1,2 yesno Maximum tested dose (oral) no yes Pediatric data Scaling to children BWT conversion 1 Safety margin approach using animal data 1 yesno Establish a mathematical relationship between adult and children data. Use it as scaling factor (eg, popPK, Pk-PD, exposure-response etc.) BSA scaling from max. Tested dose Pediatric data ye s no Establish a mathematical relationship between adult and children data. Use it as scaling factor (eg, popPK, Pk-PD, exposure- response etc.) Reference 1: Pharmacokinetics of ingested xenobiotics in children: A comparison with adults De Zwart et al, RIVM report /2002 *Rowland and Tozer Formula (Clinical Pharmacokinetics text book) or For NTI drugs (narrow theapeutic index). Toxic drugs For most drugs

Acknowledgements  Evelyne Koerper  Stephanie Bley  James McLeod  Klaus Rose  Pratapa Prasad  Melton Affrime  William Robinson  Trevor Mundel