Supplementary file:
Model-informed intermittent TDF/FTC dosing for HIV pre-exposure prophylaxis in subjects with renal impairment: a case report
L. Zino1, T.G. Jacobs1, T. Nieuwenstein1, K. Grintjes2, A. Colbers1, D.M. Burger1
Affiliation
1. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands 2. Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the
Netherlands
Correspondence:
Leena Zino, M.Sc.
Department of Pharmacy, 864 Radboudumc, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
Tel +31 24 3611111; E-mail [email protected]
Physiologically-based PK modelling
Full PK of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) were simulated in populations with varying degrees of renal impairment using PBPK modelling in Simcyp® (v20). We used existing TDF and FTC models that included both tubular secretion and glomerular secretion of the compounds [1, 2]. First, we defined the population for renal impairment by adjusting the kidney size and GFR based on default population settings in SimCyp. To reflect the reduction in tubular secretion, we reduced the number of proximal tubule cells per gram of kidney (PTCPGK) and additional clearance of tenofovir and FTC for patients with renal impairment, based on extrapolation from a virtual renally impaired population receiving lamivudine (Table S1) [3]. Then, we simulated PK data in 50 virtual healthy adults, adults with moderate renal impairment (GFR: 30-50 ml/min), and adults with severe renal impairment (GFR: 15-30 ml/min). The renal impairment groups were selected as they correspond with cut-off values used for treatment of HIV and those applied in clinical studies [4, 5]. Model performance was evaluated by comparing predicted PK in these virtual populations to observed clinical data. The populations used for the verification runs were matched based on the populations in the clinical trial (eGFR, age, and male/female ratio). Verification was deemed successful if simulated PK parameters were within 2- fold of clinical data. Finally, the intermittent PrEP regimen was simulated for 50 virtual healthy adults (2-1-1), patients with moderate renal impairment (2-0-1), and those with severe renal impairment (2-0-0), and compared to clinical data from the patient presented in this report.
Table S1. Adjusted input parameters to develop adult renal impairment populations that allow for PBPK modelling of TDF and FTC in SimCyp compared to healthy adults.
Parameter Healthy
adults
Adults GFR 30-50 mL/min
Adults GFR 15-30 Kidney Size Parameters
Baseline 15.4 8.4 5.7
BW coefficient 2.04 1.64 1.04
BH coefficient 51.8 32.8 29.8
Mech KiM Parameters
PTCPGK (millions) 60.0 26.0 19.2
#of nephrons(millions) 1.62 1.21 0.97
Systemic Clearance
Additional Cl FTC (L/h) 5.00 2.58 2.09
Additional Cl TDF (L/h) 3.60 1.85 1.50
Model verification
TDF/FTC model verification was deemed successful based on Cmax, AUC, and CL/F values (Table S2, S3).
Table S2 TDF model performance. Fold error = simulated data in a similar virtual population divided by observed data from literature. Verification was deemed successful if simulated PK parameters were within 2-fold of clinical data. Green = within 1.5-fold; Orange = within 2-fold. AUC = area-under-curve; Cl/F = oral clearance; Cmax = maximum concentration; tau = dosing interval.
Adults Healthy Moderate Renal Impairment
Dose tau = 24hr; 300mg tau = 48hr; 300mg
Simulated Observed Fold error Simulated Observed Fold error
AUC (0-tau) (mg/L*h) 1.51 1.74 0.87 4.21 5.76 0.73
Cmax (mg/ml) 0.23 0.26 0.88 0.38 0.44 0.86
CL/F (L/h) 103.57 not reported - 36.25 23.60 1.54
Observed data Wenning et al. 2008 [5] Cressey et al. 2015 [4]
Table S3 FTC model performance. Fold error = simulated data in a similar virtual population divided by observed data from literature. Verification was deemed successful if simulated PK parameters were within 2-fold of clinical data. Green = within 1.5-fold; Orange = within 2-fold. AUC = area-under-curve; Cl/F = oral clearance; Cmax = maximum concentration; SS = steady state; tau = dosing interval.
Adults Healthy Moderate Renal Impairment Severe Renal Impairment
Dose tau = 24hr; 200mg tau = 48hr; 200mg tau = 72h; 200mg
Simulated Observed Fold error Simulated Observed Fold error Simulated Observed Fold error
AUC (0-tau) (mg/L*h) 10.2 6.47 1.58 28.93 24.44 1.18 43.64 32.32 1.35
AUC (0-tau) (mg/L*h) SS 10.34 8.00 1.29
Cmax (mg/ml) 1.54 1.54 1 2.59 3.18 0.81 2.75 2.84 0.97
Cmax (mg/ml) SS 1.55 1.72 0.90
CL/F (L/h) 20.99 29.34 0.72 7.46 8.28 0.90 4.91 5.94 0.83
CL/F (L/h) SS 20.62 25.5 0.81
Observed data FDA Biopharm review FTC-106 [6] FDA Biopharm review FTC-107 [7] FDA Biopharm review FTC-107 [7]
Table S4 Simulated TDF pharmacokinetic parameters for patients with renal impairment receiving GFR-adjusted dosages. Virtual healthy subjects received 600mg TDF, followed by 300mg TDF after 24 hours and another dose of 300mg TDF 24 hours later (2-1-1 regimen); Virtual renally impaired subjects (eGFR 30-50 mL/min) received 600mg TDF, followed by 300mg TDF after 48 hours (2-0-1 regimen); Virtual severely renally impaired subjects (eGFR 15-30 mL/min) received a single dose of 600mg TDF (2-0-0 regimen).
AUC = area-under-curve; Cl/F = oral clearance; Cmax = maximum concentration; P 24hr = 24hr patient sample; P 48hr = 48hr patient sample; tau = dosing interval. *Total AUC is the sum of AUCs; total Ctrough reflects the lowest number; total Cmax reflects the highest concentration
Healthy adult population Moderate renal impaired population Severe renal impaired population 0-24hr 24-48hr 48-72hr Total* 0-24hr P 24hr 0-48hr P 48hr 48-72hr Total* 0-24hr 0-48hr 0-72hr Total*
AUC (mg/L.h) 2.537 1.368 1.368 5.273 - 7.401 3.428 10.829 - - 11.72 11.72
Ctrough (mg/L) 0.019 0.011 0.010 0.010 0.109 0.140 0.034 0.080 0.065 0.034 0.178 0.079 0.037 0.037
Cmax (mg/L) 0.469 0.244 0.244 0.469 - 0.699 0.382 0.699 - - 0.741 0.741
CL/F (L/h) 118.496 110.457 110.457 - - 40.397 43.771 - - - 25.77 -
Table S5 Simulated FTC pharmacokinetic parameters for patients with renal impairment receiving GFR-adjusted dosages. Virtual healthy subjects received 400mg FTC, followed by 200mg FTC after 24 hours and another dose of 200mg FTC 24 hours later (2-1-1 regimen); Virtual renally impaired subjects (eGFR 30-50 mL/min) received 400mg FTC, followed by 200mg FTC after 48 hours (2-0-1 regimen); Virtual severely renally impaired subjects (eGFR 15-30 mL/min) received a single dose of 400mg FTC (2-0-0 regimen).
AUC = area-under-curve; Cl/F = oral clearance; Cmax = maximum concentration; P 24hr = 24hr patient sample; P 48hr = 48hr patient sample; tau = dosing interval. *Total AUC is the sum of AUCs; total Ctrough reflects the lowest number; total Cmax reflects the highest concentration
Healthy adult population Moderate renal impaired population Severe renal impaired population 0-24hr 24-48hr 48-72hr Total* 0-24hr P 24hr 0-48hr P 48hr 48-72hr Total* 0-24hr 0-48hr 0-72hr Total*
AUC (mg/L.h) 20.602 10.454 10.454 41.510 - - 58.587 - 28.368 86.955 - - 92.065 92.065
Ctrough (mg/L) 0.036 0.020 0.019 0.019 0.323 0.290 0.015 0.090 0.158 0.015 0.957 0.080 0.010 0.010
Cmax (mg/L) 3.089 1.556 1.556 3.089 - - 5.662 - 2.839 5.662 - - 6.693 6.693
CL/F (L/h) 20.837 20.487 20.487 - - - 7.312 - 7.530 - - - 4.641 -
References
1. Liu SN, Desta Z, Gufford BT. Probenecid-Boosted Tenofovir: A Physiologically-Based Pharmacokinetic Model-Informed Strategy for On-Demand HIV Preexposure Prophylaxis. CPT Pharmacometrics Syst Pharmacol 2020; 9(1):40-47.
2. De Sousa Mendes M, Hirt D, Urien S, Valade E, Bouazza N, Foissac F, et al. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. Br J Clin Pharmacol 2015; 80(5):1031-1041.
3. Shah K, Fischetti B, Cha A, Taft DR. Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine. Curr Drug Discov Technol 2020; 17(3):387-396.
4. Cressey TR, Avihingsanon A, Halue G, Leenasirimakul P, Sukrakanchana PO, Tawon Y, et al. Plasma and Intracellular Pharmacokinetics of Tenofovir Disoproxil Fumarate 300 mg Every 48 Hours vs 150 mg Once Daily in HIV-Infected Adults With Moderate Renal Function Impairment. Clin Infect Dis 2015; 61(4):633-639.
5. Wenning LA, Friedman EJ, Kost JT, Breidinger SA, Stek JE, Lasseter KC, et al. Lack of a significant drug interaction between raltegravir and tenofovir.
Antimicrob Agents Chemother 2008; 52(9):3253-3258.
6. Elvitegravir/cobicistat/emtricitabine/tenofovir Alafenamide (E/C/F/TAF). Clinical pharmacology and biopharmaceutics review's: 2014; Available online, (accessed 2022 jan 20): From: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207561orig207561s207000clinpharmr.pdf.
7. Efavirenz [internet]. Clinical pharmacology and biopharmaceutics review's: 2014; Available online, (accessed 2022 jan 20): From:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20972biopharm_review.pdf.