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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

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Pharmaceutical Development

Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

Tallinn, Estonia

Date: 15-19 October 2007

pharmaceutical development
Pharmaceutical Development:

Bioavailability and bioequivalence in Paediatric medicine

Presenter: Jean-Marc AIACHE

Emeritus Professor,

Auvergne University,

Faculty of Pharmacy,

28 Place Henri Dunant

63000 Clermont-Ferrand, France

pharmaceutical development1
Pharmaceutical Development

Outline and Objectives of presentation

  • Definitions and relevance to paediatric medicines
  • Relevance of paediatric pharmacokinetics
  • Measurement
  • Regulatory Aspects
  • Formulation Strategies
  • Ethical considerations in design and conduct of bioavailability studies in children
definitions and relevance to paediatric medicines
Definitions and relevance to paediatric medicines


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

definitions and relevance to paediatric medicines1
Definitions and relevance to paediatric medicines


  • The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

(21 CFR 320.1. US)

comparison of definitions
Comparison of definitions
  • The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. (21 CFR 320.1. US)

(for drug product that are intended or not to be absorbed in the blood stream)

  • The rate and extent to which the active ingredient or active moiety is delivered from a pharmaceutical form and becomes available in the general circulation (CPMP/EWP/QWP/1401/98, EU)

(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.

bioavailability why
Bioavailability: why?
  • Where is the place of Bioavailability in the future of a dosage form in the human being?
technological galenicals factors of b a
Technological (galenicals!) Factors of B.A





Dissolved API

Free API

Absorbed drug


Drug Dosage


Type of DDF







Prop of API.

Drug released



Dissol. Rate

Dissolved drug


Absorbed drug

Subject, race, age,

sex, disease…,

relevance to paediatric medicines
Relevance to paediatric medicines
  • The technological factors have the same influence in Adults and children ,except for dissolution rate due to the difference of volume of G.I tract liquids for example…and taste of DF which increase the gastric secretion (Pavlov…)
  • Physiological factors influencing BD: They are fundamentally different from adults.

Age ,race, metabolism state, particularly the A.D.M.E phenomena in children

modification of absorption phenomena
Modification of absorption phenomena
  • Oral Route :Rate of intestinal absorption decreased in the newborn.
  • Gastric pH:

* 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.

  • This can explain:

*the low absorption of weak acid like Phenobarbital and Aspirin and

**a better absorption of weak basic substances.

oral route
Oral Route
  • Gastric emptying rate is decreased in the newborn
  • The half- life is about 90 minutes. At six to eight months this value reach the adults value,80 min.
  • the synthesis of biliary acid is quite of the half of adult value: This can explain the low absorption of lipid soluble substances, essentially vitamins A.,E,.D and K.
  • The bacteria in the colon come later after the birth and depend on the type of food.
  • The milk which is used largely generally reduces the absorption of some products by adsorption;
rectal route
Rectal route
  • The absorption is convenient in case of oral intolerance and overall if the drug is administered in solution, like enema for the treatment of convulsions with diazepam or midazolam.
  • The absorption is not so good after suppositories administration.
intramuscular route
Intramuscular route
  • The absorption rate is low and hazardous in the newborn due to low blood flow rate in the muscles, to low amount of muscle masses and low motor function of the baby.
cutaneous administration
Cutaneous administration
  • The skin absorption is more important in the newborn than in adults.
  • This can be explain by the elevated ratio between the skin area and the weight, and by the elevated hydratation of the stratum corneum.
  • But this route is essentially used for topical application and not for systemic activity (except for pain treatment)
  • The dosage form must be a administered

on a non injured skin .

other modifications
Other Modifications
  • Distribution Volume:

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)

  • Protein Binding
  • Evolution of metabolism organs.
  • i.e., in the newborns absorption and elimination are reduced, distribution volume increased. So the time between 2 doses is large and it is to be noted that highly protein bounded drug must be discarded.
  • i.e. in the babies, the metabolism is accelerated, distribution volume is high. So the single dose must be more elevated but dosing interval smaller than in adults
  • Do we have to do Bioavailability studies in babies and in general in children?


  • Study of all dosage forms?


question when these studies are needed
Question: When these studies are needed?
  • For new drugs, and new drug product or dosage form: clinical studies ,pharmacokinetics studies and/or BA studies
  • For generics: only Bioequivalence studies based on BA evaluation or pharmacologic or therapeutic comparisons.
new drugs
New drugs

ICH Topic E 11

  • Clinical Investigation of Medicinal Products in the Paediatric Population


General principles.
  • “Drug development programs should usually include the paediatric patient population when a product is being developed for a disease or condition in adults and it is anticipated the product will be used into paediatric population”.
clinical investigation
Clinical Investigation

The decision to proceed with the Paediatric development program for a medicinal product involve consideration of many factors, including :

  • the prevalence of the condition to be treated in the Paediatric population
  • the seriousness of the condition to be treated
  • whether the medicinal product is novel or one of a class of compounds with known properties
  • whether there are unique Paediatric indications for the medicinal product
  • the age range of pediatric patients likely to be treated with the medicinal product
  • unique Paediatric (developmental) safety concern with the medicinal product, including any nonclinical safety issue
  • potential need for paediatric formulation development
clinical investigation1
Clinical Investigation
  • “Of these factors, the most important is the presence of serious or life-threatening disease for which the medicinal products represent a potentially important advance in therapy”.
  • “It should be noted that the most relevant safety data for paediatric studies ordinarily come from adults humanexposure. Repeated dose toxicity studies, reproduction toxicity studies and genotoxicity tests would generally be available”.
  • All these studies requires adequate dosage forms: solutions etc..
clinical investigation timing of studies
Clinical Investigation: Timing of studies

. 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.

  • First case: Medicinal products for disease dominantly or exclusively affecting paediatric patient.

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

clinical investigation timing of studies1
Clinical Investigation: Timing of studies
  • Second case. :Medicinal products intended to treat serious or life-threatening disease, occurring in both adults and paediatric patient, for which there are currently no or limited therapeutic options.

If the product represents a potentially important advance in therapy, there is a need for relatively urgent and early initiation of paediatric studies.

  • Third case. :Medicinal products intended to treat other disease and conditions.

There is less urgency than in the previous cases and studies would usually begin at later phases of clinical development

clinical investigation type of studies
Clinical Investigation: Type of studies:
  • When a medicinal product is studied in paediatric patients in one region, the intrinsic (for example pharmacogenetic) and extrinsic( for example diet), factors that could impact on the extrapolation of data to other regions should be considered.
clinical investigation type of studies1
Clinical Investigation: Type of studies:

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

clinical investigation type of studies2
Clinical Investigation: Type of studies:
  • When a medicinal product is to be used in younger paediatric patient for the same indication as those studied in older paediatric patient, the disease process is similar, and the outcome of therapy is likely to be comparable, extrapolation of efficacy from older to younger paediatric patient may be possible. In such cases, pharmacokinetic studies in the relevant age groups of paediatric patients likely to receive the medicinal product, together with safety studies may be sufficient to provide adequate information for paediatric use.
  • This approach should be insufficient for medicinal product where blood levels are known or expected not to correspond with efficacy or where there is concern that the concentration-response relationship may differ between the adult and paediatric population.


clinical investigation type of studies3
Clinical Investigation: Type of studies:
  • When the comparability of the disease course or outcome of therapy in paediatric patient is expected to be similar to adults, but the appropriate blood levels are not clear, it may be possible to use measurements of pharmacodynamic effect related to clinical effectiveness to confirm the expectation of effectiveness and to define the dose and concentration needed to obtain that pharmacodynamic effect.
  • Thus a PK/PD approach combined with safety and other relevant studies could avoid the need for clinical efficacy studies.
clinical investigation type of studies4
Clinical Investigation: Type of studies:
  • For topical active product, extrapolation of efficacy from one patient population to another may be based on studies that include pharmacodynamic and / or appropriate alternative assessment. Local tolerability studies may be needed. It may be important to determine blood levels and systemic effects to assess safety.
  • Pharmacokinetic studies should be performed to support formulation development and determine pharmacokinetic parameters in different age group to support dosing recommendations.
  • Relative bioavailability comparisons of paediatric formulation with the adults oral formulation typically should be done in adults.
  • Definitive pharmacokinetic studies for dose selection across the age ranges of paediatric patients in whom the medicinal product is likely to be used shall be conducted in the paediatric population.
  • They are conducted in patients with the disease, even this may lead to high inter subject variability than the studies in normal volunteers, but the data better reflect clinical use.
  • For medicinal product with linear pharmacokinetics in adults, single dose pharmacokinetic studies in the paediatric population may provide sufficient information for dosage selection.
pharmacokinetics doses
Pharmacokinetics: doses
  • Dosing recommendations for products used in the paediatric population are usually based on milligram/kilogram body weight up to a maximum dose.
  • The dosing based on milligram/ square meter body surface present numerous errors in measuring height or length .
  • In oncology surface/area guided dosing may be necessary but extra care should be taken to ensure proper for dose calculation
pharmacokinetics protocol
Pharmacokinetics: Protocol
  • The volume of blood withdrawn should be minimized in paediatric studies.
  • Use of sensitive essays.
  • Use of laboratories experienced in handling small volume of blood.
  • Use of indwelling catheters to minimize distress.
  • Use of population pharmacokinetics and sparse sampling based on optimal sampling theory to minimize the number of samples obtained from each patient.
ethical issues in pediatric studies
Ethical issues in pediatric studies
  • The paediatric population represents a vulnerable subgroup and it is necessary to protect the rights of the study participants.
  • The recruitment of study participants should occur in a manner free from inappropriate inducement either to the parent is or the study participant.
  • As a rule the paediatric subject is legally unable to provide informed consent.

So they are dependent on their parents to assume responsibility for their participation in the study, who will give their fully informed consent.

  • Participants of appropriate intellectual maturity should personally sign and date either a separately designed written assent form or the written informed consent.
ethical issues in pediatric studies1
Ethical issues in pediatric studies
  • It is important to minimize the distress and discomfort :
  • use of topical anesthesia to place IV catheters, which have to be indwelling catheters.
  • Personnel knowledgeable and skilled in dealing with the paediatric population.
  • A physical setting with furniture, play equipment, activity, and food appropriate to the age of population.
  • A familiar environment such as the hospital or clinic where participants is normally receive their care.
  • “Bioequivalence is the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000

  • “This definition emphasizes the use of pharmacokinetic measures in an accessible biological matrix such as blood, plasma, and/or serum to indicate release of the drug substance from the drug product into the systemic circulation.

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations Food and Drug Administration October 2000

comparison of definitions1
Comparison of definitions
  • Pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose. (27 CFR 320.1(e)).
  • Two medicinal products are BE if they are pharmaceutical equivalents or pharmaceutical alternatives and if their Bioavailabilities after the administration of the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same (CPMP/EWP/QWP/1401/98, EU)
definitions cpmp ewp qwp 1401 98 eu
Definitions (CPMP/EWP/QWP/1401/98, EU)
  • Pharmaceutical equivalents:
    • Same amount active substance
    • Same dosage forms
  • Pharmaceutical alternatives:
    • Same amount of active moiety
    • In different chemical form or
    • Different dosage form
bioequivalence why
Bioequivalence : Why?
  • “Prescribability refers to the clinical setting in which a practitioner prescribes a drug product to a patient for the first time.
  • Switchabilityrefers to the setting in which a practitioner transfers a patient from one drug product to another. This situation arises with generic substitution,

“Guidance for Industry Average, Population, and Individual Approaches to Establishing Bioequivalence” Aug 1999

bioequivalence when
Bioequivalence: When
  • To compare 2 dosage forms administered by the same way, but with formulation or Manufacturing Process different ,in the same company.
  • To compare 2 dosage forms of formulation and M.P unknown: ”Generics”
what is a generic
What is a Generic
  • 1st definition given in France(1963) by the Trade Ministry:

“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

definitions cpmp ewp qwp 1401 98 eu1
Definitions (CPMP/EWP/QWP/1401/98, EU)
  • Essentially similar products:
    • Same qualitative-quantitative composition in active substances
    • Same dosage form*
    • Bioequivalent
    • *By extension for IR products the concept also applies to different oral forms (tablets and capsules) with same active substance.
    • In France all the Essentially similar product to an innovator are classified in a Generic family of” XXX”
bioequivalence on what
Bioequivalence on what???
  • On a general point of view for all dosage forms for routes of administration!!
  • For oral solutions, it is not compulsory except if there are excipients which can modify the absorption.
  • For suspensions, capsules, tablets, these in vivo studies have to be done in parallel with in vitro studies.

Methods for assessing BE1 USA

Methods for assessing BE1 UE

  • Alternatively to classical BA studies using pharmacokinetics end points to assess BE, other types of studies can be envisaged, e.g. human studies with clinical or pharmacodynamic end-points, studies using animal models or in vitro studies as long as they are appropriately justified and/or validated
  • 1.Note for guidance on the investigation of BA and BE (CPMP/EWP/QWP/1401/98, EU)
  • Pharmacokinetic study
  • Pharmacodynamic study
  • Comparative clinical study
  • In vitro study


Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations

  • The classical parameters have to be determined:
  • Both direct (in example rate constant, rate profile), indirect( for example C Max , Tmax , mean absorption time, mean residence time, C Max normalized to AUC).
  • Early exposure, peak exposure, total exposure.
  • The bioequivalence criterions are described in the official recommendations in USA and EU.
example nevirapine
Example: Nevirapine

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.

  • It has been later determined in a single dose study in 9 patients agedbetween 9 months and 14 yearsadministered after an overnight fast (3 patients per dose levelequivalent to 7.5 mg/m², 30.0 mg/m² and 120.0 mg/m²).
  • Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatricpopulation. A 4 mg/kg dose is proposed for all children regardless the age. Although no particularstudy has been performed to find the optimal lead-in dose, this dose was considered acceptableconsidering the enzyme induction to achieve initial antiretroviral activity.

The final recommended doses for the different ages are therefore the following:

  • Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by 7 mg/kg bid
  • Patients from 8 years to 16 years are 4 mg/kg once daily followed by 4-mg/kg bids.
bioequivalence compulsory
Bioequivalence: Compulsory???
  • Drug dependence and DF dependence

Solubility and

Dissolution rate In vivo

Luminal degradation


  • Same dissolution profile
  • Formulation components do not alter permeability or intestinal transit

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

bcs classification
BCS classification


Volume of aqueous buffer to dissolve the highest dose


Exemption criteria of IN VIVO studies


  • Rapidly dissolving
    • When no less than the 85% of the labeled amount of the drug substance dissolves within 30 mins using USP apparatus I (100 rpm) or II (50 rpm) in a volume of 900 mL or less in each of the following media 0.1 N HCL, (or SGF without enzymes) pH4.5 buffer, pH 6.8 buffer or SIF (without enzymes).


  • Rapid dissolution:
    • Demonstrate similarity of dissolution profile between test and reference in each of three buffers within the range of pH 1-8 at 37ºC (preferably pH 1.0, 4.6, 6.8).
    • In cases where more than 85% of the active substance are dissolved within 15 minutes, the similarity of dissolution profiles may be accepted as demonstrated.
Biowaiver: permission to use dissolution test as a surrogate of pharmacokinetic data: Dissolution test: In vitro Bioequivalence

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)

Non-NTI drugs


classify who essential drugs
Classify WHO Essential Drugs
  • Readily available data (solubility)
  • Easily Implemented Estimation (permeability)
  • Provisional Classification
who and us drugs
WHO and US Drugs


325 Medicines

260 Drugs

123 Oral IR


200 Drug Products

141 Oral

43 on WHO List

who essential drugs
WHO Essential Drugs
  • 67% of WHO IR drugs are High Solubility
  • 68% of US Top 200 drugs are HS
  • In Vitro Dissolution BE standard is applicable to the majority of WHO Drugs
  • Easily implemented, routinely conducted
what to do for bie studies in children
What to do for BIE studies in children??
  • Use of BCS for API to waive the BIE study
  • Study of the dosage form in vitro whatever the BCS of the API if there is a reference as the innovator and comparison with sharpness of the dissolution curves and results. There is a dissolution device for all the dosage form and a lot of possibility for media!!
  • BIE study in adults: the performance of the DDF can be appreciated if the API has not a special metabolism in child (or infant!). However for issue of essay (sensitivity )it could be necessary to administer 2 or more DDF, that may induce some errors in LADME and bad BIE results !!
what to do for bie studies in children1
What to do for BIE studies in children??
  • Correlation IVIVC to be developed, but no extrapolation of adult data to children, except in case of proof!!!
  • It seems better to privilege the PD bioassays than PK with sampling in children if it possible and so to facilitate the determination of exposure /activity with M.AC. than exposure /plasmatic levels, essentially for antibiotics ,antiviral, anticancer drugs.
recent examples of ba and bie trials
Recent Examples of BA and BIE trials
  • Sponsored by:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Information provided by:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Identifier:NCT00436878Purpose
  • The purpose of this study is to test the effects of large food portions on children's eating. Experiment 1 will test the effect of portion size on children's consumption of sweetened beverages; we hypothesize that serving large beverage portions will increase the amount of energy children consume from this food. Experiment 2 will test the effects of portion size on children's intake of fruits and vegetables (FV) affect intake whether such effects are moderated by children's FV preferences and; we hypothesize that serving large fruit and vegetable portions will produce increases in children's intake of these foods, particularly for children who like fruit and vegetables. Experiment 3 will evaluate how food energy density affects children's response to large portions; we hypothesize that large portions will have the greatest influence on children's energy consumption when foods are energy dense. Experiment 4 will begin to address perceptual mechanisms by which large portions affect children's eating.
Ibuprofen Effective for Acute Musculoskeletal Pain Relief in Children  CME

News Author: Laurie Barclay, MDCME Author: Charles Vega, MD, FAAFP Disclosures

Release Date: March 13, 2007; Valid for credit through March 13, 2008

Credits Available

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.

Bioavailability study results for new paediatric tablets for oral suspension, and caution against splitting adult doses
  • Polly Clayden, HIV i-Base
  • All discussion concerning obstacles to paediatric scale up - both at this conference and to date - has highlighted the lack of easily stored, low cost, age appropriate antiretroviral formulations for children.
  • As an interim measure many programmes prescribe divided adult fixed dose combinations (FDCs) but this is not without problems, and can yield suboptimal levels of nevirapine, particularly in very young children (see below). Obviously FDCs for children will be a welcome development.
Paediatric FDCs

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. [3]

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. [4]

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.”

MedlinePlus related topics:  Thyroid DiseasesGenetics Home Reference related topics:  Thyroid Diseases
  • Study Type: InterventionalStudy Design: Treatment, Randomized, Open Label, Active Control, Crossover Assignment, Bio-equivalence Study
  • Official Title: Generic vs. Name-Brand Levothyroxine: Assessment of Bioequivalence Using TSH as a Marker in Children With Permanent Hypothyroidism
  • Further study details as provided by Children's Hospital Boston:
  • Primary Outcomes: Thyroid Stimulating Hormone MeasureExpected Total Enrollment:  40
  • Study start: June 2006;  Expected completion: January 2008Last follow-up: January 2008;  Data entry closure: January 2008
  • This study is an unblinded, randomized controlled cross-over study, which involves taking 2 different forms of levothyroxine sequentially over a 16 week period. Subjects will have a total of 3 visits over this time period. At the first visit, subjects are randomized to rec

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.

  • A new way for the future and a long way to solve all the issues….
further references
Further references

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