Physiologically Based Pharmacokinetic Modelling of the Co-administration of Ritonavir-Boosted Atazanavir and Rifampicin in Children Co-treated for HIV and Tuberculosis

doi:10.21203/rs.3.rs-5068722/v1

Purpose

A dosing strategy for ritonavir-boosted atazanavir (ATV/r) to overcome the drug-drug interaction (DDI) effect with standard doses of rifampicin (10mg/ kg) was investigated in children aged between 7 and 18 years who were divided into 3 weight bands: 25-30 kg, 30-49 kg, and 50-70 kg.

Methods

We developed a paediatric physiologically-based pharmacokinetic (PBPK) model from a validated adult PBPK model with the necessary DDI components. The paediatric PBPK model was validated using relevant clinical data of ATV/r alone and rifampicin alone in children.

Results

Dose escalation to twice-daily dosing of ATV/r was predicted to boost ATV C_trough adequately. With ATV/r 300/100 mg twice daily dosing in the presence of standard doses of rifampicin, predicted ATV C_trough was higher than 150 ng/ml in over 90% of the paediatric population.

Conclusions

This model results suggests ATV/r 300/100 mg twice daily could maintain sufficient concentrations for antiviral efficacy when co-administered with standard dose of rifampicin taken once daily in children between 7 and 18 years. However, clinical studies are still warranted to confirm safety and efficacy of the dose escalation in children.

paediatrics

children

drug-drug interactions

ritonavir-boosted atazanavir

rifampicin

By 2022, 1.5 million children less than 15 years were estimated to be living with HIV [1]. Similarly, children less than 15 years make up 11% of people living with TB [2].Co-infection with TB and HIV poses serious health risks as TB is the leading cause of death in people living with HIV [3]. The World Health organization (WHO) has recommended early initiation of antiretroviral therapy for children co-infected with TB and HIV to reduce mortality [3].

Boosted protease inhibitor (PI)-based regimens are the preferred choice for children failing a dolutegravir-based regimen. Both ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted lopinavir (LPV/r) are recommended for use in children [3]. Whilst LPV/r has more child-friendly formulation options than ATV/r, it is poorly tolerated and requires twice daily administration, unlike ATV/r which is given once daily [3]. Like many other PIs, ATV is mainly metabolised by cytochrome P450 (CYP) 3A which is potently inhibited by ritonavir (RTV). So, low doses of RTV are co-administered with ATV to boost ATV exposure [4]. Conversely, rifampicin, a potent inducer of CY3A4, is a mainstay of TB treatment in children [2]. Co-administration of boosted PIs and rifampicin in people requiring treatment for both TB and HIV creates a significant drug-drug interaction (DDI). Rifampicin is known to reduce ATV and LPV exposure by 72% and 75%, respectively, during co-administration [4–6]. Based on data from a dose-escalation study, the WHO recommends doubling the dose of LPV/r when co-administered with rifampicin for children and adults [3, 6]. Co-administration of ATV/r and rifampicin is currently not recommended by the WHO in children and adults because of the absence of a safe and efficacious dosing strategy to overcome rifampicin-mediated DDI effect [3, 5].

Recent results from our mechanistic modelling study suggested that increasing ATV/r dose from 300/100 mg once daily to twice daily could overcome the DDI effect of standard dose rifampicin 600 mg once daily in adults [7]. Subsequently, a dose escalation trial (DERIVE trial, NCT 04121195), conducted in people living with HIV in Uganda, also showed that twice daily dosing of ATV/r 300/100 mg could overcome DDI in the presence of rifampicin in adults with no adverse event recorded during the short study duration [8]. A similar study in children has not been conducted to determine whether the same dosing strategy for ATV/r could overcome DDI with standard doses of rifampicin. Additionally, some studies have reported differences in the DDI effect of rifampicin on LPV/r in children when compared to adults [9, 10]. This observation highlights the risk of direct extrapolation of results obtained in adults to children and the need to investigate DDI effects in children separately.

Physiologically-based pharmacokinetic (PBPK) modelling is a mechanistic tool capable of describing drug disposition in different populations under various clinical scenarios including DDI in children [11]. The aim of this study was to develop and validate a paediatric PBPK model from the existing adult PBPK model earlier used to investigate DDI between ATV/r and rifampicin in non-pregnant adults [7]. Subsequently, the paediatric PBPK model was used to investigate dosing strategies of ATV/r that might overcome the DDI effect of standard doses of rifampicin in children between 7 and 18 years. The predicted ATV C_trough were compared against ATV protein binding-adjusted 90% inhibitory concentration (PAIC₉₀ = 14 ng/ml) and the commonly cited clinical cut-off concentration for ATV (150 ng/ml) [7].

2.1 Paediatric PBPK model development

The paediatric PBPK model for this study was developed using SimBiology® which is a product of MATLAB R2019a (MathWorks, Natick, US; 2019). The paediatric PBPK model used in this study was developed from a validated adult PBPK model with DDI component, earlier reported by Montanha et al (2022) [7]. The development workflow for the paediatric PBPK model is shown in Fig. 1. The body weight and body mass index (BMI) within the adult PBPK model were modified into values for children with ages specifically between 7–18 years using equations previously described by Rajoli et al (2018) [12]. In addition, organ and tissue weights within the paediatric PBPK model were also derived with allometric equations previously described by Rajoli et al (2018) [12–16]. Likewise, the cardiac output and organ blood flows were also as previously described by Rajoli et al (2018) [12, 17, 18]. Tables S1-S3 show the drug-specific parameters implemented in the model earlier reported by Montanha et al (2022) [7].

2.2 Paediatric PBPK model validation

The simulated anatomical and physiological characteristics were compared against literature values [12, 18]. Likewise, the simulated PK of ATV/r (administered alone) and rifampicin (administered alone) were validated with relevant clinical data in children shown in Table S4 [19, 20]. The model simulations were considered validated when the absolute average fold error (AAFE), shown in Eq. 1, was < 2 after comparisons between the summary statistics (mean or median) of the simulations and their corresponding observed clinical values.

$$\:AAFE=\:{10}^{\left|\frac{\sum\:\text{log}\frac{predicted}{Observed}}{N}\right|}$$

1

Where AAFE – absolute average fold error, N – number of data points compared, predicted – model predicted value(s), and observed – observed clinical value(s).

2.3 PK predictions of ATV/r and rifampicin coadministration in children

A virtual population of 100 children was generated for each simulation. The co-administration of the standard regimens of ATV/r and rifampicin were simulated in virtual children stratified into three distinct populations with different weight- and age-bands (Table 1). The selected the doses were derived from the WHO recommendations for the weight-based dosing of ATV and RTV for the treatment of HIV, and rifampicin for the treatment of tuberculosis [3, 21].

Table 1

Atazanavir, ritonavir, and rifampicin doses stratified by age and weight.
Age (years)	Body weight (kg)	Atazanavir dose (mg)	Ritonavir dose (mg)	Rifampicin dose (mg)
7–11	25–30	300	100	300
8–14	30–49	300	100	450
12–18	50–70	300	100	600

Co-administration of ATV/r 300/100 mg OD and standard doses of rifampicin OD was simulated in the corresponding virtual population of children described in Table 1. ATV/r 300/100 mg OD without rifampicin was also simulated in the same virtual population of children for comparison purposes. ATV PK at steady-state were analysed for each simulation and the predicted ATV C_trough at steady-state was compared against ATV PAIC₉₀ (14 ng/ml) and the commonly cited clinical cut-off concentration for ATV (150 ng/ml) for each simulation.

ATV PK during the administration of ATV/r 300/100 mg twice daily (BD) was also explored in the same children populations receiving different doses of rifampicin co-administered once daily. ATV PK at steady-state were analysed for each simulation and predicted ATV C_trough at steady-state was compared against ATV PAIC₉₀ (14 ng/ml) and the common clinical cut-off concentration for ATV (150 ng/ml).

3.1 Paediatric PBPK model validation

Validation results for the simulated anatomical and physiological characteristics of children in the model are shown in Tables S5-S7. Also, comparisons between the simulated ATV PK data with different doses of oral ATV/r and their corresponding observed clinical PK data are shown in Table 2. For ATV/r 200/100 mg OD, the AAFE values for ATV PK parameters in children were between 1.34–1.94. For ATV/r 300/100 mg OD, the AAFE values for ATV PK parameters in children were between 1.22–1.72. Thus, the AAFE values were all less than 2-fold which was the stated acceptance threshold for this study. Hence, the paediatric PBPK model was considered validated for simulating oral ATV/r PK in children with ages between 7–18 years.

Similarly, comparisons between the simulated rifampicin PK data at different sampling times with oral 13.4 mg/kg and their corresponding observed clinical PK data are shown in Table 3. For Day 2 and 10, the AAFE values for rifampicin PK parameters in children were between 1.16–1.35. Hence, the paediatric PBPK model was considered validated for simulating oral rifampicin pk in children with ages between 7–18 years.

Table 2

Validation of paediatric PBPK model for ATV PK with clinical data of different doses of oral ATV/r administered once daily in children (simulated vs observed)
PK parameter	Observed	Simulated	AAFE
ATV/r 200/100 mg once daily
C_trough (mg/L)	0.56	0.87	1.56
C_max (mg/L)	4.95	6.63	1.34
AUC_0 − 24 (mg.h/L)	43.0	83.3	1.94
ATV/r 300/100 mg once daily
C_trough (mg/L)	0.69	0.98	1.42
C_max (mg/L)	5.04	6.17	1.22
AUC_0 − 24 (mg.h/L)	46.78	80.41	1.72

Data presented as geometric mean values. AAFE – absolute average fold error; ATV – atazanavir; ATV/r – ritonavir-boosted atazanavir; C_trough – plasma concentration at the end of the dosing interval; C_max – maximum plasma concentration; AUC_0 − 24 – area under the plasma concentration time curve within 24 hours.

Observed data obtained from Deeks et al (2012) [19].

Table 3

Validation of paediatric PBPK model for rifampicin PK with clinical data of oral rifampicin 13.4 mg/kg administered once daily in children (simulated vs observed)
PK parameter	Observed	Simulated	AAFE
Day 2
C_max (mg/L)	9.40	12.7	1.35
AUC_0 − 24 (mg.h/L)	66.9	57.5	1.16
Day 10
C_max (mg/L)	10.4	12.7	1.22
AUC_0 − 24 (mg.h/L)	71.8	57.4	1.25

Data presented as geometric mean values. AAFE – absolute average fold error; C_max – maximum plasma concentration; AUC_0 − 24 – area under the plasma concentration time curve within 24 hours.

Observed data obtained from Ruslami et al (2022) [20].

3.2 Co-administration of ATV/r 300/100 mg once daily with standard doses of rifampicin taken once daily

Figure 2 shows the predicted ATV PK at steady-state during repeated once daily administration of ATV/r 300/100 mg in children with different weight-bands with and without the co-administration of rifampicin once daily. Comparing the ATV PK with and without the addition of rifampicin, the geometric mean ratios for ATV C_trough, C_max and AUC_0 − 24 were 0.01, 0.58, and 0.33, respectively in children weighing between 25–30 kg; 0.01, 0.51, and 0.28, respectively in children weighing between 30–49 kg; and 0.002, 0.47, and 0.22, respectively in children weighing between 50–70 kg. In addition, 42, 65, and 94% of the children population were predicted to have ATV C_trough below 14 ng/ml in weight-bands of 25–30 kg, 30–49 kg, and 50–70 kg, respectively. Similarly, at least 97% of the children population were predicted to have ATV C_trough below 150 ng/ml across all the weight-bands.

3.3 Co-administration of ATV/r 300/100 mg twice daily with standard doses of rifampicin taken once daily

Figure 3 shows the predicted PK of ATV at steady-state during repeated twice daily administration of ATV/r 300/100 mg in children with the co-administration of standard doses of rifampicin once daily for different weight-bands. Predicted DDI impact of rifampicin on ATV C_trough was significantly reduced with the twice daily dosing regimen of ATV/r explored in all children populations.

Comparing ATV PK between the once and twice daily administration of ATV/r alongside the respective standard dose of rifampicin, the geometric mean ratios for ATV C_trough, C_max and AUC_0 − 24 were 0.55, 0.70, and 0.69, respectively in children weighing between 25–30 kg; 0.39, 0.66, and 0.61, respectively in children weighing between 30–49 kg; and 0.25, 0.63, and 0.54, respectively in children weighing between 50–70 kg. In addition, only 4, and 9% of the children population in weight-bands of 30–49 kg, and 50–70 kg, respectively, were predicted to have ATV C_trough below 150 ng/ml.

TB is a leading cause of death among people living with HIV highlighting the need for adequate treatment for both diseases when treated concurrently [3]. This modelling study investigated dose escalation of ATV/r 300/100 mg from once daily to twice daily towards overcoming DDI effect with standard doses of rifampicin in children. The paediatric PBPK model used was built from a validated adult PBPK model with DDI modelling components which was earlier developed for investigating DDI between ATV/r and rifampicin in adults [7]. Age-related changes affecting organ weights and blood flows were incorporated into the paediatric PBPK model as previously described in literature [12]. Enzyme abundance and activities were kept at adult values as the relative expressions of most CYP enzymes in children compared to adults are expected to peak around 5 years after birth. The paediatric PBPK model was successfully validated with relevant clinical data for ATV/r and rifampicin in children [19, 20].

Co-administration of ATV/r and rifampicin was simulated in children with different weight-bands (25–30, 30–49 and 50–70 kg) and overlapping age ranges. These weight-bands were determined using the WHO recommended dosing for rifampicin and ATV/r in children [3, 21]. For each weight-band, ATV PK was simulated during once and twice daily dosing of ATV/r 300/100 mg in the presence of the respective standard rifampicin dose. Co-administration of ATV/r 300/100 mg once daily with standard doses of rifampicin once daily in children was predicted to lower ATV exposures with 67, 72, and 78% reduction in the predicted ATV AUC for children in the 25–30, 30–49 and 50–70 kg weight-bands, respectively. Likewise, 42, 65, and 94% of the children population were predicted to have C_trough below 14 ng/ml in the 25–30, 30–49 and 50–70 kg weight-bands, respectively. Generally, trough concentrations of ritonavir-boosted protease inhibitors at standard doses are known to be reduced by > 90% when taken with rifampicin [22]. Simulated ATV concentrations were predicted to be much higher with the co-administration of ATV/r 300/100 mg twice daily and the respective standard doses of rifampicin taken once daily across the different weight-bands. Within each 24-hour dosing cycle of rifampicin, the impact of rifampicin’s induction on predicted ATV PK was higher during the first 12 hours after rifampicin’s administration. Nonetheless, dose escalation to twice-daily dosing of ATV/r was predicted to boost ATV C_trough adequately. Predicted ATV C_trough during ATV/r 300/100 mg twice daily was higher than 14 ng/ml in all the children across the different weight-bands in the presence of rifampicin. Also, the lowest predicted ATV C_trough was 15-, 3.7- and 7-fold higher than 14 ng/ml in the 25–30, 30–49, and 50–70 kg weight-bands, respectively. Nonetheless, these predicted ATV C_trough fell below 150 ng/ml in 4 and 9% of the children in the 30–49 and 50–70 kg weight-bands, respectively. Interestingly, reliability of the common clinical cut-off concentration for ATV (150 ng/ml) has been questioned recently with evidence suggesting the ATV PAIC₉₀ being more reliable [8]. Predicted ATV C_max experienced the least change between the once daily and the twice-daily dosing of ATV/r in the presence of rifampicin.

Model predictions suggest increasing the dosing of ATV/r to twice daily could overcome the DDI effect of rifampicin during concurrent treatment of HIV and TB in children within the weight-bands that were investigated. Nonetheless, clinical studies are warranted to investigate twice daily dosing of ATV/r 300/100 mg in the presence and/or absence of rifampicin in children to confirm these model predictions. Similarly, the safety of this dose escalation requires further clinical investigation in children. Some evidence suggests that the risks of hepatotoxicity with adjusted doses of boosted protease inhibitors might be reduced in people living with HIV that are established on protease inhibitors prior to the introduction of rifampicin. Likewise, the sequence of introducing of ATV/r (boosted protease inhibitors) and rifampicin along with any necessary dose escalation might modulate reduce the risk of hepatotoxicity [22]. Thus, the sequence of introducing of ATV/r and rifampicin along with any necessary dose escalation to reduce the risk of hepatotoxicity in children might also need to be studied [8].

A safe and efficacious dosing strategy for ATV/r to overcome DDI effect with rifampicin would increase available treatment options for children requiring concurrent treatment for TB and HIV. Thus, the feasibility of twice daily of ATV/r 300/100 mg in overcoming the DDI effect with standard doses rifampicin is crucial. Clinical studies in children are warranted to confirm safety and efficacy of the escalated dose of ATV/r. Likewise, a similar investigation of the escalated dosing of ATV/r with rifampicin in younger children is recommended. This study reiterates the capacity of PBPK modelling to investigate various complex clinical scenarios within complex populations such as children.

Acknowledgements

This project is part of the EDCTP2 programme supported by the European Union (grant number RIA2016MC-1606-VirTUAL). CW is funded by Wellcome Trust (222075_Z_20_Z). S.A. was supported by the Duncan Norman Charitable Trust.

Funding declaration

This project is part of the EDCTP2 programme supported by the European Union (grant number RIA2016MC-1606-VirTUAL). CW is funded by Wellcome Trust (222075_Z_20_Z).

Competing Interests

Financial interests: MCM is currently a paid-employee of Bristol Myers Squibb, but her primary contributions to this study pre-date her joining the company. The remaining authors have no relevant financial or non-financial interests to disclose.

Human Ethics and Consent to Participate declarations: not applicable

Consent for publication

Not applicable

Availability of data and materials

Data supporting the findings of our study are available upon reasonable request from the corresponding author.

Author contributions

CW, MS, PD and SA designed the research. MS and MCM contributed analytical tools. SA performed research and analysed data. SA, RN, MCM, MS, PD, CO, HM and CW wrote the manuscript.

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Competing interest reported. Financial interests: MCM is currently a paid-employee of Bristol Myers Squibb, but her primary contributions to this study pre-date her joining the company. The remaining authors have no relevant financial or non-financial interests to disclose.

20240828SupplementaryInformationchildrenDDIATVrRIF1614.docx
Supplementary information Tables S1-S7 are under the supplementary information.

Physiologically Based Pharmacokinetic Modelling of the Co-administration of Ritonavir-Boosted Atazanavir and Rifampicin in Children Co-treated for HIV and Tuberculosis

Status:

Version 1

Abstract

Figures

1 Introduction

2 Methods

2.1 Paediatric PBPK model development

2.2 Paediatric PBPK model validation

2.3 PK predictions of ATV/r and rifampicin coadministration in children

3 Results

3.1 Paediatric PBPK model validation

3.2 Co-administration of ATV/r 300/100 mg once daily with standard doses of rifampicin taken once daily

3.3 Co-administration of ATV/r 300/100 mg twice daily with standard doses of rifampicin taken once daily

4 Discussion

5 Conclusions

Statements and Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1