Pharmaceutical Development. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallinn, Estonia Date: 15-19 October 2007. Pharmaceutical Development:. Bioavailability and bioequivalence in Paediatric medicine Presenter: Jean-Marc AIACHE
Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations
Date: 15-19 October 2007
Outline and Objectives of presentation
Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from the pharmaceutical form and becomes available at the site of action … (in the general circulation)”
EMEA CPMP/EWP/QWP 1401/88 date for coming in operation January 2002
(21 CFR 320.1. US)
(for drug product that are intended or not to be absorbed in the blood stream)
(practical definition for substances intended to exhibit a systemic effect)
The evaluation of BA is made by data comparison of the BA from tested product and the BA data from a solution, suspension or IV dosage form.
So this determination must be considered as a value of the performance of the drug dosage form, quite as a parameterof the dosage form.
Type of DDF
Prop of API.
Subject, race, age,
Age ,race, metabolism state, particularly the A.D.M.E phenomena in children
* no HCl in the newborn until the end of the first month
** the level of gastric secretion of adults is reached only after four to six years.
*the low absorption of weak acid like Phenobarbital and Aspirin and
**a better absorption of weak basic substances.
on a non injured skin .
The water soluble drugs will be prescribed at high doses (amino glycosides, theophyllin, aminosides, penicillin, cephalosporin, phénytoïn, vancomycin, bétalactamines …) in premature newborn.
The lipid soluble drug (diazepam, Phenobarbital…) will be prescribed at lower doses (high peak ,low VD)
ICH Topic E 11
The decision to proceed with the Paediatric development program for a medicinal product involve consideration of many factors, including :
. The timing of paediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of alternative treatments.
The entire development program will be conducted in the paediatric population except for initial safety and tolerability data, which will usually be obtained in adults. Some products may reasonably be studied only in the paediatric population even in the initial phase, for example when studies in adults who yield little useful information or expose them to inappropriate to risk
If the product represents a potentially important advance in therapy, there is a need for relatively urgent and early initiation of paediatric studies.
There is less urgency than in the previous cases and studies would usually begin at later phases of clinical development
When a medicinal product is to be used in the paediatric population for the same indication as those studied and approved in adults, the disease process is similar in adults and paediatric patients, and the outcome of therapy is likely to be comparable, extrapolation from adult efficacy data may be appropriate. In such cases, pharmacokinetic studies in all the age ranges of paediatric patient likely to receive the medicinal product, together with safety studies, may provide adequate information for used by allowing selection of paediatric doses that will produce blood levels similar to those observed in adult. If this approach is taken, adults pharmacokinetic data should be available to plan the paediatric studies
So they are dependent on their parents to assume responsibility for their participation in the study, who will give their fully informed consent.
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000
“Guidance for Industry Average, Population, and Individual Approaches to Establishing Bioequivalence” Aug 1999
“Copy of a drug product ,the production and marketing of which are allowed after the patent caducity”.
It contains the same API, the same excipients, has the same therapeutic effects and /or secondary and is administered by the same route: TRUE COPY
Methods for assessing BE1 UE
1.GUIDANCE FOR INDUSTRY
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations
Nevirapine was readily absorbed (> 90 %) after oral administration in healthy volunteers and in adultswith HIV-1 infection.
A 3-way crossover study compared the bioavailability from three production/commercialscale batches with varying dissolution profiles. All three batches were bioequivalent with respect tosystemic exposure (AUC). The significantly different values for Cmax and tmax were considered not tobe clinically relevant.
In studies 1100.1231 and 1100.896 in which the suspension was administered directly using a syringe,it was demonstrated that the suspension and tablet formulations were comparably bioavailable withrespect to extent of absorption. In study 1100.1213 the suspension was administered in a dosing cupwithout rinsing. The suspension intended for marketing was bioequivalent to the suspension usedduring clinical trials but was not bioequivalent to the marketed tablets. This could be attributed toincomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.
The final recommended doses for the different ages are therefore the following:
Dissolution rate In vivo
Amidon GL. Lennernas H. Shah VP. Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12(3):413-20, 1995
Volume of aqueous buffer to dissolve the highest dose
Exemption criteria of IN VIVO studies
High solubility, pH 1-8 (6.8)
Linear and complete absorption
Rapid dissolution (T85<30min, pH=1.0,4.6,6.8)
Excipients well established (not large doses)
Risk of therapeutic failures
High solubility, pH 1-7.5 (6.8)
High permeability (Fabs>90%)
Rapid dissolution (T85<30min, pH=1.2,4.5,6.8)
Excipients currently approved for IR Dosage Forms (FDA Inactive Ingredients List)
EMEA/CPMP and FDA/BCS
123 Oral IR
200 Drug Products
43 on WHO List
News Author: Laurie Barclay, MDCME Author: Charles Vega, MD, FAAFP Disclosures
Release Date: March 13, 2007; Valid for credit through March 13, 2008
Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians
March 13, 2007 — In a group of children randomly assigned to ibuprofen, acetaminophen, or codeine, ibuprofen was the most effective for treating the pain of acute musculoskeletal injuries, according to the results of a study reported in the March issue of Pediatrics.
"Our goal was to determine which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the most efficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries," write Eric Clark, MD, from the University of Ottawa in Ontario, Canada, and colleagues. "Although there have been studies comparing the pain relief provided by different oral analgesics in children postoperatively, there are no published randomized, controlled trials examining the use of common oral pain medications for children with acute musculoskeletal injury in the ED [emergency department]."
This study enrolled 336 children age 6 to 17 years with pain from a musculoskeletal injury to the extremities, neck, and back that occurred in the preceding 48 hours before presentation in the emergency department. These children were randomized to receive a single oral dose of 15 mg/kg of acetaminophen, 10 mg/kg of ibuprofen, or 1 mg/kg of codeine. Children, parents, and evaluators were blinded to group assignment, and the main endpoint was change in pain from baseline to 60 minutes after treatment with study medication, measured with a visual analog scale.
Of 336 patients randomized, 300 were included in the analysis of the primary outcome (100 in the acetaminophen group, 100 in the ibuprofen group, and 100 in the codeine group). Age, sex, final diagnosis, previous analgesic given, and baseline pain score were similar in the 3 groups.
At 60 minutes, improvement in pain score was significantly greater in the ibuprofen group (mean decrease, 24 mm) than in the codeine group (mean decrease, 11 mm) and acetaminophen group (mean decrease, 12 mm). More patients in the ibuprofen group achieved adequate analgesia (visual analog scale, < 30 mm) at 60 minutes than in the other 2 groups.
HIV Pharmacology Workshop: The dangers of breaking up tablets for paediatric dosing
printer friendly versionsend to friendglossarycommentYasmin Halima, Monday, May 01, 2006Further evidence that dividing adult Triomune tablets for use by children may result in under-dosing was presented last week at the HIV Pharmacology Workshop in Lisbon, and the workshop also heard the first bioequivalence data on a paediatric tablet formulation of Triomune, called Pedimune. Triomune (a fixed dose combination of stavudine (d4T), lamuvdine (3TC) and nevirapine) is the cheapest regimen available in much of sub-Saharan Africa, and is commonly prescribed to adults. Attempts have been made to estimate doses for children by halving and quartering tablets, but it is unclear if these doses are correct. A European-African study involving the Radboud University and Nijmegen University in the Netherlands, two African hospitals in Malawi and Zambia respectively and the UK Medical Research Council (MRC) was carried out. The aim of the study was to investigate whether Triomune tablets that are routinely divided for administration, deliver the same active ingredients, particularly in children who are malnourished. Tablets are difficult to split, the drugs are not equally distributed and there are no formal recommendations on how to divide them with the distinct possibility of under-dosing.
Paediatric FDCs oral suspension, and caution against splitting adult doses
At the pharmacology (PK) workshop in Lisbon earlier this year, independent investigators presented bioavailability data for Indian generic manufacturer Cipla’s Pedimune Baby and Pedimune Junior FDC tablets of NVP, 3TC and d4T, which led them to conclude that it would be acceptable to begin testing PK and dosing requirements of these formulations in African children even though the formal bioequivalence study by Cipla has not yet been completed. [1, 2]
Another Indian generic company, Ranbaxy has developed two new paediatric formulations of tablets for oral suspension (TFOS) “designed to disintegrate quickly into a uniform suspension in small volume of liquid media like water”.
A poster from Singla and co-workers from Ranbaxy described the formulation development of Triviro-LNS kid (3TC 20mg /nevirapine 35mg/d4T 5mg) and Triviro-LNS kid DS (3TC40mg / nevirapine 70mg / d4T 10mg) – which will provide NIH recommended doses of the drugs for children weighing 9-31kg. 
And in an oral presentation Manish Vermer reported findings from the company’s bioavailability study of a single dose of the Triviro-LNS kids DS formulation compared to reference propriety liquid formulations. 
The investigators reported that the tablet has: a break line, “to enhance accuracy of dosing”; “a pleasant orange flavour” and requires no specific measuring device or refrigeration. Time to dispersion is 40 seconds in a small amount of water.
The bioavailability study was an open label, single dose crossover study conducted in 36 fasting HIV negative adult males.
The investigators reported that the geometric mean ratios (% Test/Reference) of log-transformed parameters of AUC, Cmax and 90% confidence intervals were within 80 -125% interval, see Table 1.
They wrote “Therefore the two treatments were considered to be similarly bioavailable and they concluded “Ranbaxy’s novel paediatric triple ARV TFOS could be used in place of individual liquid formulations.”
Purpose oral suspension, and caution against splitting adult doses
This is a randomized, double-blind, multi-centered study to compare 6 months of medical treatment with digoxin or propranolol in infants with SVT Background: SVT is the most common sustained arrhythmia of infancy. Neither digoxin nor propranolol has been evaluated for pediatric use in a controlled trial in the context of SVT, yet both medications are used frequently.
Specific aims of the study:
To determine whether propranolol and digoxin differ in the:
Incidence of recurrent SVT in infants after 6 months of treatment with propranolol or digoxin
Time to first recurrence of SVT in infants treated with propranolol or digoxin.
Incidence of adverse outcomes in infants treated with propranolol or digoxin.
Condition InterventionPhaseSupraventricular Tachycardia in Infants Drug: digoxin and propranololPhase IIIMedlinePlus consumer health information
Study Type: InterventionalStudy Design: Treatment, Randomized, Double-Blind, Active Control, Single Group Assignment, Bio-equivalence Study
Official Title: Multicenter Study of Antiarrhythmic Medications for Treatment of Infants With Supraventricular Tachycardia
Asthma and gastroesophageal reflux disease (GERD) are common disorders, which although are not usually lethal, both have high morbidity, and high healthcare costs. Recent studies have demonstrated that asthma and GERD often co-exists, and that this co-existence is more frequent than just chance. Therefore, studies that characterize associations between these conditions, and, help in the development of interventions will positively impact the outcomes of these patients, which are critically needed.
Subjects that participate in this study are required to be between the ages of 4-11 years old. This protocol proposes to enroll 50 children with asthma, on inhaled steroids who have poor asthma control, defined on the basis of frequent symptoms, excessive beta-agonists use, or frequent asthma episodes.
The purpose of this research study is to:
Determine, whether children with symptomatic, poorly controlled, asthma assigned to treatment with a PPI( Proton Pump Inhibitor), have fewer asthma episodes than similar participants assigned to placebo for a similar duration of time
Determine whether children treated with Lansoprazole ( i.e., proton pump inhibitor) : have a longer time to first exacerbation, have improved lung function, improved asthma symptom scores, improved quality of life, decreased rescue inhaler use, or other asthma medications, reduced emergency room/urgent care/ physician office visits that are asthma related.
Determine whether a subgroup of symptomatic asthmatics, who show a greater benefit from PPI’s, can be identified.
Ranbaxy presents bioequivalence data on two paediatric fixed dose triple combination tablets
printer friendly versionsend to friendglossarycommentEdwin J. Bernard, Thursday, August 17, 2006Two fixed dose triple combination water-dispersible tablets produced by generic manufacturer Ranbaxy providing half- and quarter-doses of nevirapine, lamivudine and stavudine for paediatric use are bioequivalent to their proprietrary liquid formulations in adults, according to a study presented to the Sixteenth International AIDS Conference in Toronto on August 16th. The two formulations have already been approved by the Indian government, and have been submitted to the World Health Organisation (WHO) for inclusion on their pre-qualification list. Several recent initiatives have begun to address the issue of lack of paediatric formulations in low-income countries, first highlighted two years ago at the Fifteenth International AIDS Conference in Bangkok by Médecins Sans Frontières (MSF) director Daniel Berman.
Yu LX et al. Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm Res 2002 19(7).
Polli J.E et al. Summary Workshop Report: Biopharmaceutics Classification System- Implementation Challenges and Extension Opportunities. J Pharm Sci 2004 93(6)
Vogelpoel H. et al. Biowaiver monographs for IR solid oral dosage forms based on BCS literature data: Verapamil HCl, Propranolon HCL and Atenolol.2004 J Pharm. Sci. 93(8)
Lindenberg et al.: Classification of orally administered drugs on the WHO model list of essential medicines according to the biopharmaceutics classification system. Eur. J. Pharm. Biopharm. 58: 265-278, 2004