Pharmacokinetics in children

The study by Antwi et al. (2017) shows that the Tmax and AUC0-8 of pyrazinamide are significantly lower in a co-infection with HIV while the clearance is significantly higher in these children.

The following kinetic parameters have been observed [Arya et al., Gupta et al., McIlleron et al., Roy et al., Thee et al. and Zhu et al.]:

Cmax (one-time 30 mg/kg)	37.7-43.4 µg/ml
t½	3.5-10.9 hours
Tmax	0.75-3 hours
Cl	0.06-0.13 l/kg/hour
Vd	0.67-0.9 l/kg

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Tuberculosis (combined with other tuberculosis medication)
Oral 1 month up to 18 years and < 25 kg [5] [7] [8] [9] [10] [11] [16] 30 - 40 mg/kg/day in 1 dose. Max: 2 g/day. 1 month up to 18 years and ≥ 25 kg [5] [7] [8] [9] [10] [11] [16] 25 - 30 mg/kg/day in 1 dose. Max: 2 g/day.

Latent tuberculosis infection
Oral 1 month up to 18 years [17] 20 mg/kg/day in 1 dose. Max: 1.5 g/day. in combination with rifampicin.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Adjustment not necessary

GFR 30-50 ml/min/1.73 m2

Adjustment not necessary

GFR 10-30 ml/min/1.73 m2

Adjustment not necessary

GFR < 10 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 48 uur

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Hepatotoxicity and an increase of the transaminase values, increased uric acid concentration, anorexia, nausea, vomiting, skin abnormalities, arthralgia, fever and anaemia.

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Caution is needed in patients with renal function disorders. Regular checks of the hepatic function and uric acid levels are recommended

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

• ANTIINFECTIVES FOR SYSTEMIC USE
• ANTIMYCOBACTERIALS

DRUGS FOR TREATMENT OF TUBERCULOSIS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Antibiotics
	Rifampicin Related Medicines Menu">	J04AB02

Hydrazides
	Isoniazid Related Medicines Menu">	J04AC01

Other drugs for treatment of tuberculosis
	Bedaquiline Related Medicines Menu">	J04AK05
	Delamanid Related Medicines Menu">	J04AK06
	Ethambutol Related Medicines Menu">	J04AK02

References

1. Blumberg HM, et al, American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis, Am J Respir Crit Care Med, 2003;, 167, 603-662
2. Gupta P, et al, Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses, Br J Clin Pharmacol, 2008, 65, 423-7
3. Roy V, et al, Pharmacokinetics of pyrazinamide in children suffering from pulmonary tuberculosis, Int J Tuberc Lung Dis, 1999, 3, 133-7
4. Sánchez-Albisua I, et al, Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children, Pediatr Infect Dis J, 1997, 16, 760-3
5. Starke JR, et al, Management of mycobacterial infection and disease in children, Pediatr Infect Dis J., 1995, 14, 455-69
6. Zhu M, et al, Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis, Pharmacotherapy, 2002, 22, 686-95
7. Bayhan GI et al. , Pulmonary tuberculosis in infants less than one year old: implications for early diagnosis., Tuberk Toraks., 2011, 59(1), 36-42
8. Thee S et al. , Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations., Antimicrob Agents Chemother., 2011 , Dec;55(12), 5560-7
9. Mukherjee A et al. , Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Indian children., BMC Infect Dis. , 2015, Mar 14;15, 126
10. Nahid P et al. , Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. , Clin Infect Dis. , 2016 , Oct 1;63(7), e147-95
11. Donald PR et al. , Pyrazinamide pharmacokinetics and efficacy in adults and children. , Tuberculosis (Edinb). , 2012 , Jan;92(1), 1-8
12. Roy V et al. , Blood levels of pyrazinamide in children at doses administered under the Revised National Tuberculosis Control Program. , Indian Pediatr. , 2012, Sep;49(9), 721-5
13. Arya DS et al. , Pharmacokinetics of pyrazinamide in children with primary progressive disease of lungs. , Indian J Med Res. , 2008 , Nov;128(5), 611-5
14. McIlleron H et al. , Plasma concentrations of pyrazinamide in young children with tuberculosis. , Pediatr Infect Dis , 2011, 30, 262e5
15. Thee S et al. , Pyrazinamide serum levels in childhood tuberculosis. , Int J Tuberc Lung Dis, 2008, 12, 1099e101
16. WHO. , Guidance for national tuberculosis programmes on the management of tuberculosis in children. 2nd edition. , www.who.int, 2014
17. KNCV Tuberculosefonds. , Richtlijn Behandeling Latente Tuberculose Infectie (LTBI)., www.nvalt.nl, Juni 2006.
18. Antwi S et al., Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection, Antimicrob Agents Chemother., 2017, Jan 24;61(2)

Changes

Therapeutic Drug Monitoring

Overdose