key: cord-0287575-z1dsg07b
authors: Niu, W.-j.; Li, S.-z.; Jin, S.-s.; Lin, X.-y.; Zhang, M.-w.; Cai, W.-m.; Zhong, M.-k.; Xiang, X.-q.; Jiao, Z.
title: Investigation on the interaction between nifedipine and ritonavir containing antivirus regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis
date: 2020-05-26
journal: nan
DOI: 10.1101/2020.05.19.20106658
sha: c44bba5308994364f2e6d31b8f54ae9ed2fc604b
doc_id: 287575
cord_uid: z1dsg07b

Background and Objective Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Those patients are often treated with commonly used antiviral and antihypertensive agents concomitantly, such as ritonavir-containing regimens and nifedipine. Since ritonavir is a strong inhibitor of CYP3A, when nifedipine is combined with ritonavir-containing antiviral drugs, there is a potential risk of drug-drug interaction. This study aimed to provide guidance on nifedipine treatment during and after co-administration with ritonavir-containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. Methods A PBPK/PD model was developed for nifedipine by the software of Simcyp, and the model was verified using published data. The effects of ritonavir on nifedipine exposures and systolic blood pressure were assessed for instant-release, sustained-release and controlled-release formulations. Moreover, various nifedipine regimens were investigated when co-administrated with and withdrawing ritonavir. Results PBPK/PD models for three formulations of nifedipine were successfully established. The model predicted pharmacokinetic profiles of nifedipine were comparable to the published data. Ratios of predicted versus observed AUCDDI/AUCNifedipine of nifedipine were within 0.70- to 1.83-fold. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine by 9.82-34.35 times and the AUC by 44.94-50.77 times at steady state. Moreover, nifedipine dose reduced to 1/16 of the regular dose during ritonavir co-administration could lead to severe hypotension. Conclusions Ritonavir had a pronounced influence on the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine and ritonavir-containing regimens simultaneously.

The calcium channel blocker (CCB) nifedipine is effective in the treatment of 78 hypertension, angina pectoris and other cardiovascular diseases [1, 2] . European, the 79 United States and Chinese guidelines of hypertension treatment recommend calcium 80 channel blockers (CCB) as the first-line drug therapy [3] [4] [5] . The advantages of 81 nifedipine use are rapid onset of action and lack of central nervous system depression. 82 Moreover, comparing to the immediate release (IR) formulation, new once-daily 83 formulations reduce the frequency of nifedipine administration, and thus improve 84 patient compliance. Nifedipine is quickly absorbed after oral administration with peak 85 plasma concentrations occurring in 30 minutes for the IR formulation [6] . It is well 86 absorbed from the gastrointestinal tract, whereas the oral bioavailability of the parent 87 drug is only 45% [7] which suggests that nifedipine undergoes extensive first pass 88 metabolism along the intestine and liver [8, 9] . It is almost completely metabolized by 89 cytochrome P450 (CYP) 3A4 in human body [10] . Therefore, co-administering 90 nifedipine with the strong inhibitors of CYP3A4 may increase its plasma concentrations, 91 leading to the risk of hypotension, hyperglycemia, and conduction disturbances [11] . 

Nifedipine PBPK model development 134 The PBPK model for nifedipine was built in Simcyp ® simulator (version 16, Certara 135 Inc., Princeton, New Jersey, USA). Nifedipine is a Biopharmaceutics Classification 136 System Class II drug, with low solubility and high intestinal permeability [24] . It is 137 predominantly eliminated through CYP3A4 metabolism [24, 25] . Nifedipine 138 physicochemical properties (LogP and pKa), absorption, distribution, metabolism and 139 elimination (ADME) parameters are summarized in Table 1 . 140 The PK profiles for nifedipine were predicted using the Simcyp ® nifedipine 141 compound file, with a minimal PBPK distribution model and elimination pathway 142 characterized by enzyme kinetics. There are three available nifedipine formulations on 143 the market, namely IR, sustained-release (SR) and controlled-release (CR) formulation. 144 This study investigated all three formulations. The first order model was used to 145 describe the absorption process of nifedipine IR. For the SR and CR nifedipine, the oral CR and SR formulation were obtained from literature [27] and package insert of 149 Adalat ® [28] , respectively. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 26, 2020 simulated as a surrogate for the RTV-containing regimens [35] . In addition, the PBPK 175 model of RTV has been already verified by simulating its inhibition effects on the PK 176 profiles of CYP3A4 substrates [36] . Thus, the RTV model was not herein verified.

IR nifedipine at 10 mg with repeated dose administration every 12 hours (Q12H)

178 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) were also simulated. Considering no consensus for the use of nifedipine in patients 182 receiving RTV, PK profiles at different dose levels of nifedipine was simulated to 183 investigate the optimal dose during the co-administration with RTV.

After RTV was discontinued, 2 different dose regimens were investigated. One is 185 to use reduced-dose nifedipine, and the other is to restore to the original dose of 186 nifedipine. Taking IR tablets as an example, in the first regimen, nifedipine at a lower 187 dose (5 mg Q12H) or an extended dosing interval (10 mg Q24H) was taken for 5 more 188 days after the last dose of RTV, followed by a return to an original regimen (10 mg 189 Q12H). Moreover, lower dose of nifedipine (1.25 mg, 1/4 of the minimum specification 190 of IR nifedipine tablets) was investigated. Since chewing or crushing before swallowing 191 SR or CR tablets is not allowed, dose less than 30 mg or 60 mg was not assessed. In the 192 second regimen, the regular dose of nifedipine (10 mg Q12H) was taken immediately 193 after the last dose of RTV. The detailed dose adjustment scenarios are shown in Table   194 3. Due to the limitation of software, the dose amount of SR and CR tablets cannot be Studies have demonstrated that it is more important to control systolic blood 198 pressure (SBP) than diastolic blood pressure (DBP) [37] , and SBP is a better predictor 199 of cardiovascular risk than DBP in most of patients treated with antihypertensive 200 agents [38] . Therefore, only SBP was employed in the PBPK/PD modeling. A Emax 201 model developed by Shimada et al. [39] was linked to the PBPK to investigate the effect where E, Emax, EC50 and C represent the reduction in SBP, the maximum reduction in 206 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106658 doi: medRxiv preprint SBP, nifedipine concentration at 50% maximum effect and nifedipine concentration, 207 respectively.

The Emax and the EC50 were -35 mmHg and 35 nM for therapeutic dose in the 209 previous report, respectively [39] . However, in reported cases of nifedipine overdose, 210 the SBP of the patients would decrease about 50 mmHg [6, 40, 41] . Therefore, in this 211 study, the Emax value was increased to -50 mmHg to fit the maximal SBP decrease based The second scenario was designed to investigate how to adjust the dose regimen of 231 nifedipine after the withdrawal of RTV. For this scenario, two dosing regimens were 232 examined, (1) adjusted dosage regimen was continued for 5 more days after the last 233 dose of RTV; (2) the regular regimen was resumed immediately after RTV was stopped.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106658 doi: medRxiv preprint predicted AUC ratio was 1.45-fold of the observed AUC which indicated good 261 predictive performance. Figure 4 shows the observed and predicted values for CR 263 nifedipine PK profiles after a single oral dose administration in the healthy volunteers.

The predicted Cmax and AUC ratios were within 1.46-fold of the observed data. 265 Therefore, the PBPK model for CR formation showed a good descriptive and predictive 266 performance.

Nifedipine-RTV DDI 268 The final PBPK model was used to predict changes in CYP3A4 enzyme abundance and 269 nifedipine plasma PK profiles after the co-administration with RTV over time. As 270 shown in Figure 5 , the CYP3A4 in the liver and intestinal were maximally deactivated 271 within three days after the co-administration of RTV (100 mg Q12H), which suggested 272 there was a strong DDI between nifedipine and RTV. Figure 6 shows the predicted PK 273 profiles of three formulations nifedipine over time following the dosing schedules listed 274 in Table 3 . Both the Cmax and AUC increased significantly due to CYP3A4 inhibition CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106658 doi: medRxiv preprint within 0.87-1.14 ( Table 7) . Thus, the current nifedipine PD model showed good 288 predictive performance. For scenario 1, Figure 9 shows the PD profiles of regular dose of nifedipine 299 combined with RTV. For an individual taking a regular nifedipine dose combined with 300 100 mg Q12H RTV, the predicted dynamic SBP decrease was up to 47 mmHg, which 301 might be a critically low blood pressure. Moreover, nifedipine at a reduced dose during 302 RTV co-administration was unable to maintain SBP in normal range (Figure 10 ). 303 Therefore, the combined use of nifedipine and RTV-containing regimens is not With the outbreak of viral infections such as COVD-19, MERS and SARS, the antiviral 312 effect of RTV-containing regimens has received increasing attention [16, 45] . 313 Hypertensive patients are often potential susceptible population [46, 47] and require 314 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 26, 2020. nifedipine. To the best of our knowledge, this is the first systematic study to investigate 318 the DDI between nifedipine and RTV-containing regimens by using PBPK/PD analysis.

Previously published PBPK modeling of nifedipine mainly focused on the drug 320 formulations [23, 49] or special populations [50] [51] [52] . The nifedipine model developed Nifedipine undergoes significant first-pass metabolism by CYP3A in the both 331 intestine and liver [53] , thus resulting in significantly enhanced in vivo exposure of the 332 drug when administered together with strong irreversible CYP3A4 inhibitor like RTV.

The inhibitory potency of RTV in vivo has been shown to be equivalent to or greater 334 than ketoconazole which is a strong index CYP3A inhibitor for DDI studies [54] . The The PBPK/PD analysis was once used to investigate dose adjustment 350 recommendations for amlodipine during and after co-administration of RTV by 351 Mukherjee, et al [35] . The analysis suggested that resuming a full dose of amlodipine is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted May 26, 2020. TID, three times a day; Q8H, every 8 hours; QD, once daily; IV, intravenous; PK, pharmacokinetic; PD, pharmacodynamics Table 3 Clinical scenarios used in the nifedipine PBPK model simulation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106658 doi: medRxiv preprint Figure 9 Model prediction of SBP changes in the drug-drug interaction (DDI) magnitude of nifedipine and ritonavir (RTV) over multiple days. (A) IR nifedipine 10 mg every 12 hours (Q12H) × 3 days + (nifedipine 10 mg Q12H + RTV 100 mg Q12H) × 14days+ nifedipine 10 mg Q12H × 10 days. (B) SR nifedipine 30 mg Q12H × 3 days + (30 mg Q12H +RTV 100 mg Q12H) ×14 days+ nifedipine 30 mg Q12H × 10 days. (C) CR nifedipine 60 mg Q24H × 3 days+ (60 mg Q24H + RTV 100 mg Q12H) ×14 days+ nifedipine 60 mg Q24H × 10 days. The red and black solid lines represent the PD curves of combined nifedipine with RTV and nifedipine alone, respectively. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106658 doi: medRxiv preprint Figure 10 PD simulation results of nifedipine dose adjustment in different scenarios after RTV discontinuation. (A) IR nifedipine 10 mg every 12 hours (Q12H) × 3 days + (5 mg Q12H + RTV 100 mg Q12H) × 14 days+ nifedipine 5 mg Q12H ×5 days + nifedipine 10 mg Q12H × 1 day. (B) IR nifedipine 10 mg Q12H × 3 days + (5 mg Q12H + RTV 100 mg Q12H) ×14 days+ nifedipine 10 mg Q12H × 6 days. (C) IR nifedipine 10 mg Q12H × 3 days + (10 mg Q24H + RTV 100 mg Q12H) ×14 days + nifedipine 10 mg Q24H × 5 days + nifedipine 10 mg Q12H × 1 day. (D) IR nifedipine 10 mg Q12H × 3 days + (10 mg Q24H + RTV 100 mg Q12H) ×14 days+ nifedipine 10 mg Q12H × 6 days. (E) SR nifedipine 30 mg Q12H × 3 days + (30 mg Q24H + RTV 100 mg Q12H) × 14 days + nifedipine 30 mg Q24H × 5 days + nifedipine 30 mg Q12H × 1 day. (F) SR nifedipine 30mg Q12H × 3 days + (30 mg Q24H + RTV 100 mg Q12H) × 14 days + nifedipine 30 mg Q12H × 6 day. (G) CR nifedipine 60 mg Q24H × 3 days + (60 mg Q48H + RTV 100 mg Q12H) × 14 days + nifedipine 60 mg Q24H × 5 days + nifedipine 60 mg Q24H × 1 day. (H) CR nifedipine 60 mg Q24H × 3 days + (60 mg Q48H + RTV 100 mg Q12H) ×14 days + nifedipine 60 mg Q24H × 6 days. The open square symbols correspond to the mean observed values. Red and black lines represent predicted values for nifedipine with and without co-administration of RTV, respectively.

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