# Presentation: 736289

## Clinical Pharmacology Perspectives of Pediatric Dosing of Over-The-Counter (OTC) Cough and Cold Medications

**Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee**
**Silver Spring, Maryland**
**October 18-19, 2007**
**Partha Roy, Ph.D. **
**Senior Clinical Pharmacologist**
**Office of Clinical Pharmacology**
**Office of Translational Sciences**

**Center for Drug Evaluation and Research**** **

## Outline

**Issues raised in citizens petition**
**Ontogeny of renal and hepatic (metabolic) clearance mechanisms with age**
**Available pediatric PK data for OTC cough and cold drugs**
**Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution**
**Pediatric drug development: FDA’s current approach**
**Summary**

**Notes:**
This is the outline of my presentation. First I am going to briefly describe the issues raised in the Citizen’s petition and understand the basis of the petition from CP perspective, specifically what we know about systemic exposure of OTC cough and cold drugs and the factors that influence drug exposure. Clearance is the single most critical PK parameter that impacts drug exposure.
Keeping that in mind, I will discuss the ontogeny or in other words development of renal........
Then we will take a look at the systemic exposure data in children for 3 OTC cough and cold drugs that are available to us
Following that, I will address the high concentrations noted in post-mortem reports and try explain the contribution of post-mortem drug re-distribution.
Then, I am going to spend some time explaining the current practice of pediatric drug development specifically addressing the FDA’s current thinking on the requirement of pediatric PK studies with a relevant example.
Finally, I will conclude with a overall summary of the discussion 

## Citizen Petition

**Raised significant concerns about the safety and efficacy of cough and cold medications in children 6 years and younger**
**Requested FDA to re-label these products to state that these products should not be used for the treatment of cough and cold in children under 6 years of age**

**Notes:**
Let me briefly highlight the two critical bullet points from the citizen’s petition under discussion. Then read from the slides.

## Basis for the petition

**Reports of deaths and serious adverse events in which drugs commonly found in OTC cough and cold preparations were detected at very high concentrations mostly in infants and toddlers**
** **
**The absence of specific dose and dosing interval information on the label for children under the age of 2 years constitutes a safety hazard in an age range highly vulnerable to overdose**

**Notes:**
As we already know, these are the basis for the citizen petition. 
Read the slides.

## Outline

**Issues raised in citizen’s petition**
**Ontogeny of renal and hepatic (metabolic pathways) functions with age**
**Available PK data for OTC cough and cold drugs**
**Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution**
**Pediatric drug development: FDA’s current approach**
**Summary**

**Notes:**
As for any other drugs in general, OTC cough and cold drugs undergo elimination from the body via renal and/or metabolic clearance pathways. Next, I will discuss the development or functional maturation of renal and metabolic pathways with age, or in other words, ontogeny of clearance pathways.

## Clearance pathways

| Drugs | Class | Clearance |  |
| --- | --- | --- | --- |
|  |  | Renal | Metabolic |
| Pseudoephedrine | Decongestant | Major (55-75%) | Minor |
| Guaifenesin | Expectorant | Minor | Major (unknown CYPs) |
| Dextromethorphan | Anti-tussive | Minor | Major (CYPs 2D6, 3A4, 2B6) |
| Chlorpheniramine | Anti-histamine | Minor | Major (CYPs 2D6 & 2C19) |
| Brompheniramine | Anti-histamine | Minor | Major (unknown CYPs) |
| Diphenhydramine | Anti-histamine | Minor | Major (CYPs 2D6, 1A2, 2C9 & 2C19) |

**Notes:**
Before getting to ontogeny of clearance mechanisms, let’s look at the clearance pathways of some of the representative OTC cough and cold drugs. There are 2 broad clearance pathways, namely renal and metabolic. PSE is primarily cleared unchanged via urine while others undergo extensive metabolism mediated by a multitude of cytochrome P450s as you can see from this table. 

## Ontogeny of clearance mechanisms: Renal Clearance (e.g. Pseudoephedrine)

*Hayton WL (2002) AAPS PharmSci **2 (1) article 3 (http://www.aapspharmsci.org)*

**Renal maturation complete by 2 years of life**

**Glomerular Filtration**

**Active Secretion**

**Renal Blood flow**

**RFP: Renal Function Parameter**

- 2 years

**Notes:**
First let’s look at the ontogeny of renal clearance, as in theory, renal maturation and growth impact drug exposure, if the drug is primarily cleared via kidney. In a recent publication, a model was developed that characterized the maturation and growth of the renal function parameters (RFPs). In the graph on the right, model predicted BW-normalized renal function parameter relative to adult value in the y-axis was plotted against age in the x-axis. As shown here, BW normalized GF and AS begin to develop immediately after birth, reach adult value and then at some point exceeds the adult rates before it starts to decline again.  

## Ontogeny of clearance mechanisms: Hepatic Clearance (Dextromethorphan as an example)

**Ontogeny of clearance mechanisms: Hepatic Clearance (Dextromethorphan as an example)**

**Notes:**
Let’s now look at the maturation of hepatic clearance with Dextromethorphan as an example. This example is also relevant for today’s discussion since this is a widely used OTC anti-tussive agent that falls under the class of drugs under discussion.

## Impact of CYP2D6 polymorphism on drug exposure: Dextromethorphan

- Adopted from* Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516*

|  | CYP2D6
EM | CYP2D6
PM* |
| --- | --- | --- |
| Cmax (ng/mL) | 2.4
(0.5 – 5.9) | 207
(182 – 231) |
| T1/2
(hr) | 3.4 | 24 |

- * 5-10% of Caucasians, 1-3% of Asians
**EM:** extensive metabolizers
**PM:** poor metabolizers

- Dextromethorphan (DM) PK in adults

**Notes:**
The figure on your right illustrates metabolic pathways of DM. DM is metabolized by cytochrome P450 2D6 and 3A4 enzymes followed by glucuronide conjugation. CYP2D6 is believed to be the primary metabolic pathway for oral DM clearance and has been implicated in the metabolism of many other OTC cough and cold medications. This enzyme is polymorphically expressed in humans where the systemic exposure in PM phenotypes is about 100-fold greater than in EM phenotypes consistent with the half-life differences between the two populations. Besides PM phenotypes, there exist a wide spectrum of subtypes within the EM category such as intermediate, rapid and ultra-rapid. The incidence of PM phenotypic expression is about 5-10% in Caucasians and about 1-3% in asians. CYP2D6 genetic polymorphic expression is believed to be the primary cause for large inter-individual variability that we observe with DM metabolism in adults. This same phenomenon would be applicable to children as well and would likely result in large inter-individual variability that has been aptly illustrated in the next slide.

Page down twice to get animation.

## Ontogeny of CYP2D6 in the 1st year of life: Dextromethorphan (DM) / Dextrorphan (DX) urinary ratio as probe 

- Adopted from* Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516*

** ****No apparent age-related differences in CYP2D6 activity from 2 wks to 1 y of age**
** ****Large inter-individual variability ~ CYP2D6 genetic polymorphism**

**Notes:**
Attempt has been made as recently as this year by Blake and co-workers to characterize ontogeny of Dextromethorphan metabolism after oral administration in the first year of life. CYP2D6 activity is measured by the urinary DM/DX ratio. DM/DX ratio, on average, did not change from 2-weeks of life to 1 year, suggesting that the maturity of CYP2D6 enzyme is complete within the first 2 weeks of life. However, large inter-individual variability was observed for each time-points and is attributed to CYP2D6 polymorphism that I discussed in the previous slide. This data did not include PMs, still the variability is significant due probably to the inclusion of different EM subtypes. 
However, this data should be considered with caution due to several factors: 1) limited utility of DM/DX ratio to detect subtle changes in DM clearance, this ratio is more suited for dramatic changes seen with polymorphism; 2) different rate and extent of maturation of competing metabolic pathways such as CYP3A4 and phase II DMEs. These observations made it impossible to reach a definitive conclusion on CYP2D6 maturity during the first year of life.

## Ontogeny of CYP3A4: Midazolam as a probe

*de Wilt et al. (1999) Clin. Pharmacokinet 37: 485-505*

**CYP3A4: gradual increase after birth acquiring 3/4****th**** of adult activity by 2 y**
**Midazolam clearance in 2-15y > adults**

**Notes:**
The other important drug-metabolizing P450 which catalyzes number of cough and cold drugs is CYP3A4. As shown here, the maturation of 3A4 activity with age has been investigated in vivo utilizing oral clearance of Midazolam, a widely accepted probe drug for CYP3A4 enzyme activity. As illustrated by this plot, CYP3A4 exhibits a gradual increase in enzyme activity following birth in children. It has been shown that – 
On average, 40% of CYP3A4 activity attained by 1 yr and 75% activity attained by 2 years of life
In contrast, BW normalized midazolam clearance in 2-15y old, on average, is greater than in adults; this phenomenon has also been shown with other CYP3A4 substrates in the literature.

The main objective of the last three slides that I have shown you is to give you a rough idea of the dramatic changes and uncertainties in drug clearance in very young children due mostly to independent rate and extent of maturation of clearance pathways in addition to genetic polymorphism with specific enzymes such as 2D6.

## Ontogeny of other CYPs: 1A, 2B6, 2C, 2D6, 3A5, 2E1 
Ontogeny of Phase II enzymes (e.g. UGT)
Ontogeny of drug transporters 
Effect of diet (breast feeding vs. formula feeding) on the ontogeny of drug metabolizing enzymes
Effect of pH: Gastric (absorption) and urinary (elimination)

**Ontogeny of Phase II enzymes (e.g. UGT)**
**Ontogeny of drug transporters **
**Effect of diet (breast feeding vs. formula feeding) on the ontogeny of drug metabolizing enzymes**
**Effect of pH: Gastric (absorption) and urinary (elimination)**

**Additional factors impacting drug exposure:****Limited to lack of information**

**Notes:**
Apart from what I discussed already, there are other additional factors that affect the clearance, thereby exposure of drugs in children; many of which are poorly understood at present. These include but not limited to:
1. Ontogeny of other drug metabolizing P450s,
2. Ontogeny of Phase II enzymes that might impact exposure
3. Ontogeny of drug transporters which seem to gain importance in the last few years
4. A recent publication from Dr. Greg Kearns group demonstrating effect of diet on the maturation of CYPs1A2 and 3A4 enzymes
5. Effect of pH: gastric pH that can impact drug absorption while elimination can be influenced by urinary pH.

## Summary of development of clearance pathways 

** ****Renal:**
**Renal maturation complete by 2 years**
** ****Metabolic:**
**Each drug metabolizing enzymes (DMEs) demonstrate an independent rate and pattern of maturation**
**Genetic polymorphism of DMEs impacts drug exposure in children**
**Large inter-individual variability in metabolic clearance in children**

**Notes:**
So, to summarize what we have learnt regarding the development of clearance pathways: read the slide.

## Outline

**Issues raised in citizen’s petition**
**Ontogeny of renal and hepatic (metabolic pathways) functions with age**
**Available PK data for OTC cough and cold drugs**
**Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution**
**Pediatric drug development: FDA’s current approach**
**Summary**

**Notes:**
Read the 3rd bullet point.

## OTC Monograph Dosing in Children:Current Practice

**Extrapolated from dosing in adults**
**Wide margin of safety**
**Based on age: convenient**
**Stratification mimics body weight**

| Age | ≥ 12 y | 6 – 11 y | 2 – 5 y | < 2 y |
| --- | --- | --- | --- | --- |
| Mean weight (kg) | 60 | 31 | 17 | 7.5 – 12.5* |
| Monograph Dose:
Decongestant, Expectorant, Antitussive | adult dose | 1/2 of
adult dose | 1/4 of
adult dose | Consult a doctor |
| Antihistamine | adult dose | 1/2 of
adult dose | Consult a doctor** | Consult a doctor |

- * Range		** Professional labeling available

**Notes:**
Before doing that, I would briefly look at the current pediatric dose recommendations for OTC cough and cold drugs. Decongestant, expectorant and anti-tussives are dosed down to 2 years while anti-histamines are dosed down to 6 years. Children dosing is fraction of adult dosing i.e. 1⁄2 the adult dose for 6-11y olds, 1⁄4 the adult dose in 2-5y olds. This approximately mimics dosing based on average body weight for a particular age-range, realizing that a 2 year old can be very different from a 5 year old with respect to body weight. Professional labeling is available below the age of 6 for anti-histamines. The labeled recommendation for children below 2 is to consult a doctor. I would like to point out that these drugs are generally regarded as safe and efficacious and exhibit a wide margin of safety.

## Mean (CV%) Pseudoephedrine single dose PK in adults and children(Cross-study comparisons)

| PK parameters | Pediatrics (<2y) | Pediatrics (2-5y)
(rhinitis patients)
N = 7 | Pediatrics (6-11y)
(healthy)
N = 28 | Adults (18-44y)
(healthy)
N = 25 |
| --- | --- | --- | --- | --- |
| Dose (mg) | _ | 15 | 30 | 60 |
| AUC (ng.hr/mL) | _ | 1292 (41) | 1735 (27) | 2424 (26) |
| Cmax (ng/mL) | _ | 179 (17) | 218 (24) | 254 (21) |

- Note: Data obtained from Clinical Pharmacology Reviews of NDA 21-373 (Children’s Advil Cold Suspension) and NDA 21-374 (Advil Cold Sinus Liquigels)

**Mean (CV%) Pseudoephedrine single dose PK in adults and children****(Cross-study comparisons)**

**Systemic exposure in 2-11y children NMT adults**
**No PK data in children less than 2 years of age**

**Notes:**
Now I will present available PK data on 3 of the OTC drugs in the next few slides. One of the OTC decongestants for which we have good PK data down to age of 2 years is PSE as shown in the table. Following monograph suggested dosing, the mean systemic exposure in children as evidenced by peak plasma concentration and AUC, is numerically lower than in adults, although this is a cross-study comparison. No PK data is available for children less than 2 years of age for which there is no labeled dosing recommendation.

## Mean (CV%) Chlorpheniramine single dose PK in adults and children(Cross-study comparisons)

| PK parameters | Pediatrics (<6y) | Pediatrics (6-11y)
(rhinitis patients)
N = 30 | Adults (18-44y)
(healthy)
N = 29 |
| --- | --- | --- | --- |
| Dose (mg) | _ | 2 | 4 |
| AUC (ng.hr/mL) | _ | 131 (52) | 194 (76) |
| Cmax (ng/mL) | _ | 7.3 (4.4) | 8 (1.3) |

- Note: Data obtained from Clinical Pharmacology Reviews of NDA 21-587 (Children’s Advil Allergy Sinus Suspension)

**Systemic exposure in 6-11y children NMT adults**
**No PK data in children less than 6 years of age**

**Notes:**
Another example where a cross-study comparison is made is anti-histamine CHLOR. In this case, peak plasma concentrations are similar but AUC for children 6-11yrs old is numerically lower compared to adults. Similar to PSE, there is no PK data in children less than 6 where there is also no labeled dosing instruction.

## Mean Brompheniramine single dose PK in adults and children(Cross-study comparisons)

| PK parameters | Pediatrics (<6y) | Pediatrics (6–11y)
N = 14 | Adults
N = 7 |
| --- | --- | --- | --- |
| Dose (mg/kg) | _ | 1.3 | 1.3 |
| AUC (ng.hr/mL) | _ | 127 | 293 |
| Cmax (ng/mL) | _ | 7.7 | 11.6 |

- Adopted from* Simons et al. (1999) J Allergy Clin. Immunol. 103: 223-26*

**Systemic exposure in 6-11y children NMT adults**
**No PK data in children less than 6 years of age**

**Notes:**
While PSE and CHLOR pediatric PK data were from NDA submission, BROM PK data presented here is obtained from the literature and has not been reviewed by the Agency. Again, Cross-study comparison shows that on average, systemic exposure in children 6-11 years as evidenced by AUC appears to be numerically less than that in adults. Again, there is no exposure data in children less than 6 years old.

## Focus on Clearance (CL/F)

**Notes:**
Clearance is one of the most important PK parameters that determine systemic exposure. Here is the oral clearance data collected across multiple studies in different pediatric age groups compared to adults. BW normalized oral clearance has been found to be relatively greater in children compared to adults. Assuming similar fraction bioavailable between adults and children, this data generally explains the relative exposure of these drugs shown in the previous 3 slides.
In summary, based on the available PK data, this is, what we observe –the recommended labeled dose in children down to 2 years for PSE and 6 years for CHLOR and BROM generally should not produce concentrations above those noted in adults. 

## Outline

**Issues raised in citizen’s petition**
**Ontogeny of renal and hepatic (metabolic pathways) functions with age**
**Available PK data for OTC cough and cold drugs**
**Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution**
**Pediatric drug development: FDA’s current thinking**
**Summary**

**Notes:**
Read the 4th bullet point.

## C:P ratio (measure of post-mortem redistribution) for OTC cough and cold drugs

- site & timing of post-mortem blood collection
- type of biological matrix
- sample processing
- physicochemical characteristics of the drug: pka, volume of distribution

| Drugs | C:P ratio* |
| --- | --- |
| Chlorpheniramine | 3.1 |
| Dextromethorphan | 2.0 |
| Diphenhydramine | 2.3 |
| Pseudoephedrine | 1.5 |

- * C:P ratio = heart blood : peripheral blood ratio

- Factors influencing post-mortem drug redistribution

*Reference: Leikin JB and Watson WA. (2003) Clinical Toxicology, 41, 47-56.*

**Notes:**
Normally, post-mortem blood sampling was done from the cardiac area, which may not accurately predict the ante-mortem peripheral blood concentration. Higher the C:P ratio, higher the post-mortem redistribution. Here is the list of C:P ratios available for a handful of OTC cough and cold drugs from the literature. The data shown in the table suggest that this phenomenon can explain up to a maximum of 3-fold greater exposure seen in post-mortem reports but it is certainly not enough to account for exceedingly high post-mortem blood levels that were reported in some of the cases. Factors that influence C:P ratio include: read the slides

## Outline

**Issues raised in citizen’s petition**
**Ontogeny of renal and hepatic (metabolic pathways) functions with age**
**Available PK data for OTC cough and cold drugs**
**Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution**
**Pediatric drug development: FDA’s current approach**
**Summary**

**Notes:**
Read the 5th bullet point.

## FDA’s Current Approach:Objectives of Pediatric PK studies

**Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population states the following:**
**...****..****“****Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendation****”**
**Guidance for Industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products states the following:**
**...****.. ****“****In general, pharmacokinetic studies in the pediatric population should determine how the dosage regimen in the pediatric population should be adjusted to achieve approximately the same level of systemic exposure that is safe and effective in adults”**

**Notes:**
Let’s state the objectives of pediatric PK studies that were incorporated in several guidances that came out of the agency at different times. Example: ICH E11 guidance (include in your briefing package) states that “....”. Also from the Pediatric PK draft guidance, it is noted that “.....”

## FDA’s Current ApproachBridging efficacy data in an adult population to a pediatric population

- Reference: FDA’s Guidance for Industry (2003), Exposure-Response Relationships — Study
- Design, Data Analysis, and Regulatory Applications

**Notes:**
Over the past decade, the agency has adopted an approach to obtain bridging efficacy data in children using a pediatric decision tree. Based on a good understanding of disease pathophysiology, if and only if the following two assumptions of similar disease progression and similar response to intervention are true, then PK along with safety can provide a reasonable path to arrive at pediatric dosing based on systemic exposure. If these two assumptions are not true, large efficacy trials along with safety and PK data would be needed. These would be the type of studies needed if a drug was to be developed for children today and a dose recommendation for children need to be optimized.

## Key Considerations for Pediatric PK studies

**Monotherapy: single ingredient evaluation **
**Single and multiple dose evaluation**
**Adequate number of subjects within each age group**
**Range of doses within each age group**
**Sparse sampling for population PK approach**
**Adequate collection of covariate data (age, BW, gender)**

**Notes:**
If one has to conduct pediatric PK studies with the objective of optimizing dosing recommendations in children, here are the key considerations for such studies that may include traditional PK with extensive sampling and/or Population PK with sparse sampling.
1. Here are the key considerations for pediatric PK studies
2. For most part, multiple dose evaluation would be preferable, however, single dose evaluation may be sufficient in some cases,
3. There must be adequate number of subjects within each age group. The exact number of subjects to provide enough confidence in the estimates would depend upon the variability around clearance and volume of distribution terms.
4. It is preferable to test range of doses to better grasp differences in PK across doses, if any.
5. For younger children, mostly under 2 years, due to obvious difficulty in carrying out studies in that population in general, population PK approach is often employed using sparse sampling strategy. Advanced tools are now available to arrive at optimal blood sampling for the purpose.
6. Last but not he least, adequate collection of covariate data is important to identify any significant covariate that impact clearance and volume terms.

## Lessons learned from FDA’s decade-long pediatric initiatives

**Outcome of well-designed pediatric PK/Safety studies:**
**Critical labeling changes that include unique pediatric dosing**
**Focus on drug clearance and its variability in children**
**Pediatric dosing not always obtained by simply applying BW or BSA based calculations to the adult dose **
**Systemic exposure in children not always predictable based on prior adult information**

**Notes:**
Decade long pediatric initiatives from the agency since FDAMA of 1997 have led to submission of several pediatric PK and safety studies across various therapeutic areas. These studies led to: read the slides.

## Optimizing Pediatric Dosing: Desloratadine (Clarinex®) as an Example

**Optimizing Pediatric Dosing: ****Desloratadine (Clarinex****®****) as an Example**

| Age Group | Cmax | AUC | Dose q.d. (mg) |
| --- | --- | --- | --- |
| Adults | 2.3 (51) | 48.4 (54) | 5 |
| 6-11y | 2.23 (35) | 55.5 (100) | 2.5 |
| 2-5y | 2.68 (50) | 45.1 (56) | 1.25 |

| Age Group | CL/F (L/hr) | Predicted* pediatric q.d. dose (mg) |
| --- | --- | --- |
| Adults | 137 (58) | 5 |
| 1-2y | 35.5 (51) | 1.29 (0.63-1.96) |
| 1⁄2-1y | 27.8 (35) | 1.01 (0.66-1.37) |

- *CLpredicted / CLadult x adult dose

**Dose determination from traditional PK analysis (NDA 21300)**

**Notes:**
This is an example of optimizing pediatric dosing for desloratadine, a second-generation prescription anti-histamine. Pediatric dosing is based on achieving similar exposure between adults and children and demonstrating adequate safety in children down to 6 months of age. Here traditional PK approach with extensive PK sampling was utilized to arrive at dosing down to 2 years as shown in the table at the top. Below the age of 2 years down to 6 months, pediatric dosing was predicted based on population PK analysis utilizing sparse sampling strategy. Based on the population mean clearance estimates, the pediatric dose that would provide a similar exposure as that in adults following a 5-mg dose was determined to be 1.01 for 6 mo. to 1 year old children and 1.29 mg in children 1-2 y of age. This modeling and simulation exercise allowed the sponsor to arrive at more precise dosing in children down to 6 months.

## Optimizing Pediatric Dosing: Desloratadine (Clarinex®) as an Example

_**Dosing Recommendations:**_
**Adults and children ****≥****12 years:** 		5 mg once daily
**Children 6 to 11 years of age:** 		2.5 mg once daily
**Children 12 months to 5 years of age:** 	1.25 mg once daily
**Children 6 to 11 months of age:** 		1.0 mg once daily

**Optimizing Pediatric Dosing: ****Desloratadine (Clarinex****®****) as an Example**

**Notes:**
Therefore, the final labeling recommendations are: read the slides. It is worthwhile to point out here that though the dosing in children down to 2 years mimics the monograph-like fractional dosing algorithm, collection of age-appropriate PK data helped the sponsor precisely define age sub-groups and suggest unique dosing in younger children. This was only possible due to the use of advanced PK modeling and simulation tools. So, the bottom line is: if a drug is to be developed today, we do have some advanced PK tools that we did not have 30 years back which can be employed today to determine pediatric dosing provided we have relevant PK data.

## Summary (1)

**No pediatric PK data for a large number of OTC cough and cold drugs**
**Based on the data we have, PSE, CHLOR and BROM monograph doses DO NOT appear to exhibit greater drug exposure in children relative to adults**
**As in adults, drug clearance is highly variable in children and not readily predictable based on prior adult information**

**Notes:**
Now to the overall summary: read the slides.

## Summary (2)

**Factors impacting clearance mechanisms in children: **
**ontogeny**
**genetic polymorphism**
**Post-mortem drug redistribution may partly explain high post-mortem levels in reported cases**
**To optimize pediatric dosing of OTC cough and cold drugs: should additional PK studies be conducted and if so, for which ingredients and what ages? **

## Acknowledgements

**Office of Clinical Pharmacology /    Division of Clinical Pharmacology II**
**Emmanuel (Tayo) Fadiran, Ph.D.**
**Wei Qiu, Ph.D.**
**Suresh Doddapaneni, Ph.D.**
**Chandrahas Sahajwalla, Ph.D. **
**Sally Choe, Ph.D.**
**Abimbola Adebowale Ph.D.**

## Back-Up Slides

## Example of Optimal Pediatric Dosing (1) Zosyn®: Application of Pop PK Analysis

- Adopted from* Tornoe et al. (2007) **Int. J. Antimicrob. Agents, 30, 320–324.*

- Zosyn® is Piperacillin (PIP) /Tazobactam (TAZ), an IV antibacterial combination product
- Eliminated via kidney
- Comparable adult exposure as a basis for optimizing pediatric dosing
**Pediatric dosing incorporated clearance maturation rate below the age of 9 months**

*Data from 2 pediatric PK/safety studies*

**Notes:**
Let me show you an example of a drug (Zosyn) recently approved in children and how the pediatric dosing recommendation was developed. This drug product is a combination IV antibacterial and both components are primarily eliminated via urine. The basis for optimizing pediatric dosing was comparable adult exposure for children. Population PK analysis was used to incorporate renal clearance maturation rate to arrive at dosing in infants. At 9 months of age, the dosing rate should be 80% of the dosing rate for kids older than 9 months. At 2 month, the dosing rate should be 48% of the dosing rate for kids older than 9 months. 

## Example of Optimal Pediatric Dosing (2) Zosyn®: Application of Pop PK Analysis

- Adopted from* Tornoe et al. (2007) **Int. J. Antimicrob. Agents, 30, 320–324.*

**Dosing recommendation:**
** **
_**Adults and children weighing >40 kg:**_** 3.375 g every six hours totaling 13.5 g (12.0g PIP / 1.5g TAZ) per day.**
_**Children **__**≥ 9 months up to 40 kg:**_** 100 mg PIP / 12.5 mg TAZ per kg, q 8h**
_**Children 2 to < 9 months:**_** 80 mg PIP / 10 mg TAZ per kg, q 8h**

**Example of Optimal Pediatric Dosing (2) Zosyn****®****: Application of Pop PK Analysis**

**Notes:**
The final labeling recommendations are: read the slides. Overexposure of the drug for children 2 to <9 months was accepted due to wide margin of acceptable safety and to provide a convenience for dosing that can be followed easily. In addition there are efficacy concerns if doses are lowered. This type of optimization is possible taking into account various factors provided we have PK/safety data in appropriate age-groups of children.

## Ontogeny of CYP3A4 in the 1st year of life: Fractional urinary recovery of 3-hydroxymorphinan (3HM) 

**Metabolic shift from DX (CYP2D6 metabolite) to 3HM (CYP 3A4 metabolite)**

**Ontogeny of CYP3A4 in the 1****st**** year of life: ****Fractional urinary recovery of 3-hydroxymorphinan (3HM)**** **

**Notes:**
On the contrary, CYP3A4 activity appears to increase more slowly throughout the first 12 months as indicated by the solid line. The plot here indicates that 3HM, which is the CYP3A4 metabolite, becomes the predominant urinary metabolite beyond 6 months of age. This observed increase in fractional molar recovery of CYP3A4 metabolite at the expense of CYP2D6 metabolite suggests a metabolic shift in primary DM metabolism from O-demethylation to N-demethylation and is consistent with the known time course of CYP3A4 maturation in the literature as indicated by the next slide.