Rifampicin pharmacokinetics in children under the ... - IngentaConnect

INT J TUBERC LUNG DIS 19(4):440–445 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.13.0819

Rifampicin pharmacokinetics in children under the Revised National Tuberculosis Control Programme, India, 2009 A. Arya,* V. Roy,* A. Lomash,† S. Kapoor,† A. Khanna,‡ G. Rangari* Departments of *Pharmacology and †Paediatrics and ‡Chest Clinic, Maulana Azad Medical College, Lok Nayak Hospital, New Delhi, India SUMMARY O B J E C T I V E : To evaluate serum levels of rifampicin (RMP) in children with tuberculosis (TB) at doses administered according to India’s Revised National Tuberculosis Control Programme (RNTCP) 2009 report. M E T H O D : Prospective, open label, non-randomised single-dose study in 20 children aged 5–12 years. S E T T I N G : The out-patient chest clinic of a tertiary care hospital, New Delhi, India. R E S U LT S : The median RMP dose administered was 9.56 mg/kg (range 9–12.64). Peak RMP concentration (Cmax) attained was 6.24 lg/ml (range 5.44–7.61) at time to Cmax of 3.5 h (range 3–4). RMP levels were significantly lower at 2, 3 and 4 h in children administered ,10 mg/kg

than those who received 710 mg/kg (P , 0.05). A positive correlation between the RMP dose administered and Cmax was observed (r2 ¼ 0.748). RMP Cmax was ,8 lg/ml in all patients, a level considered too low for therapeutic efficacy. C O N C L U S I O N S : Low serum concentrations of RMP were attained in children under the RNTCP 2009 weight band system. Peak RMP levels appear to be lower and the single dose elimination half-life shorter in children than in adults. To optimise treatment outcomes, revisions in RMP dose in children should take into consideration agerelated differences in pharmacokinetics. K E Y W O R D S : RMP; pharmacokinetics; children; India; RNTCP; tuberculosis

RIFAMPICIN (RMP) is a major component of all anti-tuberculosis regimens. Studies in adults have demonstrated dose-related efficacy with regard to early bactericidal activity and long-term clinical outcomes.1–4 The RMP dose is a critical determinant in the overall efficacy of anti-tuberculosis regimens including RMP. A peak RMP concentration of 8–24 lg/ml after 600 mg administered to adults has been proposed as a target concentration.5 It has also been suggested that a peak RMP concentration of ,8 lg/ ml should be considered low and ,4 lg/ml as very low for therapeutic efficacy.6 Age-related differences in peak serum concentrations of RMP have been observed with the same mg per kg dose.7–14 Children prescribed RMP at a dose of 10 mg/kg body weight had lower concentrations than adults who received a similar dose. Poor treatment outcomes have been associated with low RMP concentrations in children with TB.11 Under India’s 2009 Revised National Tuberculosis Control Programme (RNTCP) report, RMP was administered at a dose of 10 mg/kg body weight (range 8–12 mg/kg) administered thrice weekly to children according to weight band. According to this

system, children weighing ,30 kg were categorised under four weight bands (Table 1).15 A combi-pack of anti-tuberculosis drugs was available for each band. However, according to the 2009 RNTCP system, some children received RMP at a dose of ,10 mg/kg. The World Health Organization (WHO) has recommended daily RMP 10–20 mg/kg body weight for children.16 Dose recommendations for anti-tuberculosis drugs for children have recently been revised and weight bands reformulated under RNTCP 2013 (Table 2).17 According to the new guidelines, the RMP dose for children has been increased to 13–17 mg/kg body weight, to be administered thrice weekly. It will take time, however, before the new guidelines are implemented countrywide. As RMP pharmacokinetics vary with age, it is important that adequate pharmacokinetic and clinical outcome data be available at the time of dose revisions. Data on serum RMP levels attained with the doses administered according to the RNTCP 2009 weight band system in North Indian paediatric patients are inadequate. We conducted the present study to observe serum RMP levels among children in

Correspondence to: Vandana Roy, Department of Pharmacology, Maulana Azad Medical College and Associated Hospitals, Bahadurshah Zafar Marg, New Delhi 110 002, India. Tel: (þ91) 99686 04283. Fax: (þ91) 11 2323 5574. e-mail: roy. [email protected] Article submitted 15 November 2013. Final version accepted 23 November 2014.

RMP pharmacokinetics in Indian children

441

Table 1 Dose of anti-tuberculosis drugs for children to be administered thrice weekly according to the RNTCP 2009 weight band system, India Weight band number

Weight kg

Rifampicin mg

Isoniazid mg

Pyrazinamide mg

Ethambutol mg

1 2 3 4

6–10 11–17 18–25 26–30

75 150 225 300

75 150 225 300

250 500 750 1000

200 400 600 800

RNTCP ¼ Revised National Tuberculosis Control Programme.

RNTCP 2009 weight bands 2 and 3 and their therapeutic outcome at 6 months.

METHODS An open-label, prospective, non-randomised singledose study was conducted in children newly diagnosed with tuberculosis (TB) attending the chest clinic in Lok Nayak Hospital, New Delhi, India. The study was approved by the hospital’s institutional ethics committee. Written informed consent was provided by parents or guardians of all the children and by all subjects aged .7 years. Subjects A total of 20 children in the 5–12 years age group, newly diagnosed with pulmonary or lymph node TB, were enrolled in the study. TB diagnosis was based on relevant clinical history, physical examination, chest X-ray, Mantoux test results and fine-needle aspiration cytology of accessible lymph nodes, wherever required. Patients with normal haematological, hepatic and renal functions were included. Children with severe TB requiring hospital admission, other diseases and history of any concomitant or long-term drug intake were excluded from the study. Study design Patients fulfilling the inclusion criteria were admitted 1 day before the start of the study to the paediatric ward of Lok Nayak Hospital. After overnight fasting, a single dose of RMP was administered at 6 am. Children weighing 11–17 kg (weight band 2) were given a single oral 150 mg dose of RMP, while those weighing 18–25 kg (weight band 3) were adminis-

tered a single oral 225 mg dose of RMP, according to the RNTCP 2009 guidelines for intermittent treatment of TB in children. RMP was supplied by Lupin Limited (Mumbai, India) to the Government of India. All doses were from the same batch. A standard breakfast and lunch were given respectively 2 h and 6 h after RMP administration; regular anti-tuberculosis treatment began 24 h later. The patients were followed up for 6 months to determine therapeutic outcomes. Sample collection Venous blood samples (1.5 ml) were collected at 1, 2, 3, 4, 6, 8 and 12 h in ethylenediaminetetraacetic acid coated tubes. Plasma was separated within 1 h and stored at 208C until RMP estimation. Ascorbic acid (0.5 mg/ml) was added to each tube to prevent RMP oxidation. Assay method RMP concentration was estimated using high-performance liquid chromatography as proposed by Hemanth Kumar et al.18 The calibration curve for RMP in plasma was found to be linear over the concentration range of 0.5–10 lg/ml, with a correlation coefficient (r) of 0.998. Under the chromatographic conditions of this method, RMP was detected at a limit of detection (LOD) of 0.34 lg/ml. The limit of quantification (LOQ) was estimated at 0.5 lg/ml. The intra- and inter-day variations were respectively 6.5–8.7% and 7.8–9.7%. RMP recovery ranged from 99.34% to 100.8%. The overall accuracy of the method ranged from 96.5% to 100.5%. There were four samples below LOQ, one at 1 h and three at 12 h. These were included in the pharmacokinetic analysis.

Table 2 Dose of anti-tuberculosis drugs for children to be administered thrice weekly according to the RNTCP 2013 weight band system, India Weight band number

Weight kg

Rifampicin mg

Isoniazid mg

Pyrazinamide mg

Ethambutol mg

1 2 3 4 5 6

6–8 9–12 13–16 17–20 21–24 25–30

100 150 200 250 300 400

100 150 200 250 300 400

250 400 500 650 750 1000

200 300 400 500 600 800

RNTCP ¼ Revised National Tuberculosis Control Programme.

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The International Journal of Tuberculosis and Lung Disease

Table 3

Demographic profile and baseline characteristics of all patients (n ¼ 20)

Patient characteristic Age, years Male:female Weight, kg Height, cm MAC, cm Haemoglobin (g %) TLC, x103/mm3 ESR, mm/h Plasma bilirubin, mg % SGOT, IU/l SGPT, IU/l Plasma alkaline phosphatase, KA0 Total protein, g % Plasma albumin, g % Blood urea, mg % Plasma creatinine, mg %

Group 1 Median (range)

Group 2 Median (range)

P value

Normal ranges*

9 (6–10) 2:6 20.6 (15–22.4) 118.5 (110–123) 11.65 (10–12) 10.2 (8–11.5) 14 (7.7–20) 30 (19–40) 0.9 (0.3–1) 16 (15–18) 16 (10–21) 19 (9–23) 6 (3.5–7) 3.5 (2.5–4.5) 25 (19–28) 0.55 (0.3–0.9)

12 (6–12) 2:10 24.2 (15.2–25) 124 (109–127) 12.15 (10.9–12.5) 10.8 (10.1–12.1) 11.5 (6–24) 26.5 (22–32) 0.65 (0.5–1.1) 17 (14–22) 13.5 (10–22) 16.5 (10–27) 6.15 (5.2–6.8) 3.6 (3–5) 23.5 (15–32) 0.6 (0.2–0.8)

0.06 — 0.04 0.13 0.04 0.04 0.5 0.5 0.52 0.19 0.45 0.9 0.25 0.54 0.64 0.68

— — — — — 11–18 4–11 0–20 0.5–1.2 10–40 10–40 3–20 6–8 3.5–5.5 15–30 ,1.4

* Reference values of the Biochemistry Laboratory, Lok Nayak Hospital, New Delhi, India. MAC ¼ mid-arm circumference; TLC ¼ total leucocyte count; ESR ¼ erythocyte sedimentation rate; SGOT ¼ plasma glutamate oxaloacetate transaminase; IU ¼ international unit; SGPT ¼ plasma glutamate pyruvate transaminase.

Pharmacokinetic analysis Pharmacokinetic parameters, peak plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration vs. time curve from 0 to 12 h (AUC0–12), and zero to infinity (AUC0–‘), elimination half-life (t1/2), clearance (Cl/f) and volume of distribution (Vd/f) were calculated. Patients were divided into two groups: those who received .10 mg/kg RMP (Group I) and those who received ,10 mg/kg RMP (Group II). Serum levels and pharmacokinetic parameters in both groups were compared. Noncompartmental analysis was used to calculate the pharmacokinetic parameters for RMP using WinNonlin Professional version 5.1.2 (Pharsight Corp, Mountain View, CA, USA). Statistical analysis Values are expressed in median and range. The baseline investigations, plasma RMP concentrations and pharmacokinetic parameters for Groups I and II

Figure 1 RMP plasma concentration over 12 h in Group I (n ¼ 8, continuous line) and in Group II (n ¼12, dotted line). Values are expressed as mean 6 SEM. RMP ¼ rifampicin; SEM ¼ standard error of the mean.

were compared using the Mann-Whitney U-test for unpaired data by IBM SPSS 20 software (IBM Corp, Armonk, NY, USA). Pearson’s correlation coefficient was determined between the RMP dose and the peak concentration attained. P , 0.05 was considered significant.

RESULTS All 20 patients completed the study. The demographic profile of patients in both groups is shown in Table 3. The body weight, mid-arm circumference and haemoglobin levels of Group II patients were higher than those of Group I patients. Three patients were in weight band 2 and 17 in weight band 3. In terms of mg/kg body weight doses, 12/20 patients received RMP ,10 mg/kg body weight and 8 received RMP .10 mg/kg. The mean RMP concentrations at different times are shown in Figure 1. RMP concentrations were significantly lower in Group II than in Group I at 2, 3 and 4 h (P , 0.05). A good correlation (r2 ¼ 0.748) was observed between RMP dose and the peak RMP concentrations attained (Figure 2). The peak RMP concentration was ,8 lg/ml in all patients (Figure 2). The median peak RMP concentration in 20 children was 6.24 lg/ml (range 5.44–7.61) at a Tmax of 3.5 h (range 3–4). The RMP t1/2 was 2.38 h (range 1.80–2.84), Vd was 0.96 l/kg (range 0.67–1.21) and RMP Cl was 6.19 l/h (range 3.99–7.09). The AUC0–12 and AUC0–‘ were respectively 33.34 lg.h/ml (range 29.73–36.13) and 35.57 (range 31.71–38.75). The individual pharmacokinetic parameters, Cmax, Tmax and AUC, are shown in Table 4. The difference between the AUC 0–12 of the two groups was statistically significant (P , 0.05). At 6 months of treatment, 19 patients had achieved cure. An unfavourable outcome, treatment failures, i.e., failure of


Figure 2 RMP Cmax in relation to single oral RMP dose per kg body weight. The line indicates a linear relation between the dose and Cmax in all patients. RMP ¼ rifampicin; Cmax ¼ peak plasma concentration.

sputum conversion after 5 months of treatment, was observed in one patient who had received RMP ,10 mg/kg body weight. Her Cmax (5.83 lg/ml) was relatively low within her group and her AUC0–12 (29.73 lg.h/ml) among the lowest in both groups.

DISCUSSION Awareness of the need to base dose recommendations in children on pharmacokinetic and pharmacodynamic data obtained in children is increasing.19–22 Few pharmacokinetic studies in children have been performed due to ethical considerations. Although anti-tuberculosis drug dose recommendations for children in India have undergone revisions (RNTCP 2009,15 RNTCP 201317), there are very few pharTable 4

macokinetic data on Indian children to support the revisions. RMP efficacy is related to serum concentrations, and concentrations ,8 lg/ml are considered too low for therapeutic efficacy.6 Serum RMP concentrations are a surrogate marker for the concentration of RMP at the site of action. In this study, peak RMP concentrations were ,8 lg/ml in all patients. In a recent study conducted among children in Chennai, India, the RMP concentrations were ,8 lg/ml in 90% of the children included.11 However, as RMP exhibits auto-induction, steady state concentrations of RMP are likely to be even lower than those observed in this single-dose study. The ages of the study patients ranged from 6 to 12 years. It is likely that in children aged ,6 years, these doses may result in still lower RMP concentrations, as serum RMP concentrations in younger children are reported to be lower than in older children when RMP is administered at 10 mg/kg body weight.10 Children aged 1–3 years had a significantly lower peak concentration and RMP exposure than other age groups for the same dose (P , 0.05).10 Peak RMP concentration was sub-therapeutic (,8 lg/ml) in the majority of the children. It has been shown that although 15 mg/kg RMP improved drug exposure, young children were still under-dosed, suggesting that the RMP dosages need to be re-evaluated in children of different ages.9 A positive correlation between RMP dosage and peak RMP concentrations was observed in this study. The antimycobacterial action of RMP is related to serum concentrations. Various studies have shown a dose-related increase in the early bactericidal activity (EBA) and sterilising activity of RMP.3 The EBA is important because a high EBA rapidly renders the

Pharmacokinetic parameters (Cmax, Tmax and AUC0–12) for RMP in children (n ¼ 20)

Patient pharmacokinetics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

443

Age years

Sex

Weight kg

RMP dose mg/kg

Cmax lg/ml

Tmax h

AUC0–12 lg.h/ml

10 8 10 9 10 9 6 9 12 12 12 12 12 6 12 11 10 12 6 11

Female Female Female Female Male Female Male Female Female Female Male Female Male Female Female Female Female Female Female Female

20.6 17.8 21 20 22.4 20.6 15 20.8 24.4 24.2 25 24 25 16 24.2 23.9 23.2 24.9 15.2 24.7

10.9 12.64 10.71 11.25 10.1 10.92 10 10.81 9.2 9.3 9.0 9.37 9.0 9.37 9.3 9.41 9.7 9.1 9.8 9.1

6.84 7.61 6.56 7.26 6.63 6.94 7.26 7.3 5.83 5.44 5.96 6.09 6.11 6.3 6.26 5.69 6.22 5.44 5.83 5.78

3 3 4 4 3 3 4 4 4 3 4 4 4 3 4 4 3 3 3 3

33.555 35.255 35.34 34.92 35.76 33.125 36.13 32.23 29.725 30.97 35.28 34.485 34.595 32.025 32.4 32.155 35.665 30.97 30.325 29.995

RMP ¼ rifampicin; Cmax ¼ peak concentration; Tmax ¼ time to peak concentration; AUC0–12 ¼ area under the plasma concentration vs. time curve from 0 to 12 h.

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The International Journal of Tuberculosis and Lung Disease

patient less infectious, reducing the risk of drug resistance and accelerating clinical improvement. RMP exhibits concentration-dependent killing, with the rate of bacterial killing increasing as the concentration of antibiotic increases.23 As antituberculosis treatment is given thrice weekly in India, it is important that RMP concentrations be such as to inhibit mycobacterial growth for a sufficient period before the next dose is administered. The significant difference in the serum RMP concentrations between Groups I (RMP .10 mg/ kg) and II (RMP ,10 mg/kg dose) at 2, 3 and 4 h may affect clinical outcomes in patients. The mean Tmax in this study was 3.5 h. A Tmax of 3– 4 h in children and 1.5–2.5 h in adults have been reported,8,24,25 and may indicate delayed drug absorption in children. Delayed absorption of RMP in children has been described in previous studies.8,24 The elimination half-life appears to be similar to that in previous studies in children and is lower than in adults.6,26 In our study the RMP Cl/f in children was lower and the Vd/f higher than in adults. It has been suggested that there is an inverse relationship with age for Vd/f and a direct relationship for plasma clearance; this pattern reflects developmental changes occurring during the period of growth.27 Reasons for low RMP levels in children include a difference in absorption, higher hepatic metabolic capacity and a larger volume of RMP distribution than in older children and adults.7,27,28 The variability of pharmacokinetic parameters was low in this study. A possible reason could be the fact that the majority of the patients were aged 9–12 years. Data on the optimal maximum serum RMP concentration in children are lacking. In adults, the proposed serum drug concentration for optimal antimycobacterial action in adults given 600 mg RMP daily is reported to be 8–12 lg/ml.6 However, this is obtained with daily treatment, while treatment is administered thrice weekly in India. No data on the optimal levels of maximum serum RMP concentration in children on thrice-weekly treatment are available, and it is difficult to comment on the adequacy of the RMP levels attained in this study. Although the precise therapeutic range for RMP is not known, RMP shows profound concentrationdependent activity, and higher concentrations are thus more desirable.29 Study limitations This study had some limitations: 1) the sample size was small, with 20 patients; this was due to ethical considerations, as the study involved repeated blood sampling in children; 2) serum RMP levels and RMP pharmacokinetics were determined after a single dose; in clinical practice, RMP is administered with other anti-tuberculosis drugs for several months and induces its own metabolism (auto-induction) by

stimulating the activity of CYP450 enzymes; 3) clinical outcomes among the study patients were not determined beyond treatment completion at 6 months; 4) no data on therapeutic levels for RMP in children on thrice-weekly treatment are available; and 5) the inclusion of children from all weight bands could have provided us with more information.

CONCLUSION Low levels of RMP were obtained in children under the RNTCP 2009 weight band system. As the optimal peak concentration for RMP is considered to be between 8 and 24 lg/ml, lower concentrations could lead to treatment failure and development of antituberculosis drug resistance. In the Indian context, studies of RMP levels in children, administered alone and in combination with other anti-tuberculosis drugs, are required — particularly if RMP is administered intermittently — and correlated with clinical outcomes. This is imperative for the optimisation of RMP dosage in children. To achieve this aim, the study should be repeated using RNTCP 2013 dosing. Acknowledgements The authors thank M Kelaivani, Scientist, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India, for her assistance in statistical evaluation. The authors would also like to thank all the patients and their families, and the health care workers of Lok Nayak Hospital. Conflicts of interest: none declared.

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RESUME O B J E C T I F : Evaluer les taux sanguins de rifampicine (RMP) chez des enfants tuberculeux a` des doses administrées selon le Programme National révisé de Lutte contre la Tuberculose (RNTCP) de 2009, Inde. S C H E´ M A : Etude prospective, ouverte, nonrandomisée a` dose unique chez 20 enfants ag´ ˆ es de 5 a` 12 ans. C O N T E X T E : Une consultation externe de pneumologie d’un hopital ˆ de soins tertiaires a` New Delhi, Inde. R E´ S U LT A T S : La dose médiane de RMP administrée e´ tait de 9,56 mg/kg (fourchette 9–12,64). La concentration plasmatique maximale (Cmax) de RMP obtenue e´ tait de 6,24 lg/ml (5,44–7,61) au temps Tmax de 3,5 h (3–4). Les niveaux de RMP a` 2, 3 et 4 h e´ taient significativement plus faibles chez les enfants qui avaient

re¸cu ,10 mg/kg par rapport a` ceux qui avaient re¸cu 7 10 mg/kg (P , 0,05). On a observé une corrélation positive entre la dose de RMP administrée et la Cmax de RMP (r2 ¼ 0,748). La Cmax de RMP e´ tait ,8 lg/ml chez tous les patients, ce qui est considéré comme faible pour une efficacité thérapeutique. C O N C L U S I O N S : Le système d’échelle de poids du RNTCP 2009 a abouti a` des faibles concentrations de RMP chez les enfants. Les pics de concentration de RMP apparaissent plus faibles et la demi-vie d’une dose unique plus courte chez les enfants que chez les adultes. Pour optimiser les résultats du traitement, il faut revoir les doses de RMP chez les enfants en tenant compte des différences de pharmacocinétique en fonction de l’âge. RESUMEN

O B J E T I V O S: Evaluar las concentraciones sangu´ıneas de rifampicina (RMP) que se alcanzan en los ninos con ˜ tuberculosis (TB), cuando se definen las dosis administradas seg un ´ el sistema de categor´ıas en funcion ´ del peso del Programa Nacional Revisado de Control de la Tuberculosis (RNTCP) del 2009 en la India. M E´ T O D O S: Fue este un estudio prospectivo, abierto, no aleatorizado de dosis unica ´ en 20 ninos ˜ de 5 a 12 anos ˜ de edad. M A R C O D E R E F E R E N C I A: La consulta ambulatoria de un hospital de atencion ´ terciaria, en Nueva Delhi, India. R E S U L T A D O S: La mediana de la dosis de RMP administrada fue 9,56 mg/kg (9–12,64 mg/kg). Se obtuvo una concentracion ´ sangu´ınea ma´xima (Cmax) de RMP de 6,24 lg/ml (5,44–7,6 lg/ml) en un tiempo ma´ximo de 3,5 h (3–4 h). Las concentraciones de RMP a

las 2, 3 y 4 h fueron significativamente inferiores en los ´ con los ninos ˜ que recibieron ,10 mg/kg en comparacion que recibieron 710 mg/kg (P , 0,05). Se observo´ una correlacion ´ positiva entre la dosis de RMP administrada y la Cmax (r2 ¼ 0,748). La Cmax de RMP fue ,8 lg/ml en todos los pacientes y esta concentracion ´ se considera baja para lograr la eficacia terapéutica. C O N C L U S I O N E S: Se obtuvieron bajas concentraciones sangu´ıneas de RMP en los ninos al aplicar la pauta ˜ posologica ´ por categor´ıas en funcion ´ del peso del RNTCP 2009. Las concentraciones ma´ximas de RMP parecen ser inferiores y la semivida de eliminacion ´ ma´s corta en los ninos que en los adultos. Con el fin de ˜ optimizar los desenlaces terapéuticos se deben revisar las dosis de RMP que se administran a los ninos, tomando ˜ en consideraci on ´ las diferencias farmacocine´ ticas relacionadas con la edad.