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. 2018 Sep;84(9):1950-1969.
doi: 10.1111/bcp.13625. Epub 2018 Jun 19.

Physiologically-based pharmacokinetic model of vaginally administered dapivirine ring and film formulations

Katherine Kay  1 , Dhaval K Shah  1 , Lisa Rohan  2   3 , Robert Bies  1   4
Affiliations

Physiologically-based pharmacokinetic model of vaginally administered dapivirine ring and film formulations

Katherine Kay et al. Br J Clin Pharmacol. 2018 Sep.

Abstract

Aims: A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film.

Methods: A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration-time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions.

Results: The DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29 079 and 33 067 mg h l-1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l-1 ) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range.

Conclusions: HIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female-controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre-exposure prophylaxis can be evaluated.

Keywords: antiretrovirals; pharmacokinetics; pharmacometrics.

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Figures

Figure 1
Figure 1
The structural compartments of the physiologically‐based pharmacokinetic model. The compartments represent the ring or film, the vaginal fluid, tissues and organs; connecting arrows represent blood supplies (solid black), elimination of drug (dotted black), passive movement of un‐ionized drug (blue) and active movement of ionized drug (green)
Figure 2
Figure 2
Dapivirine concentration–time profiles following administration of two vaginal rings (Group A dosing regimen in 21) measured in the (A) vaginal fluid, (B) plasma, (C) epithelium tissue and (D) stromal tissue. The first ring was inserted for 28 consecutive days and, upon removal, followed by a 3‐day period without a ring. The second ring was inserted for 28 days before removal. The black line represents the DPV concentration of a single patient simulated using the physiologically‐based pharmacokinetic parameters from Tables 1 and 2. The coloured lines represent the arithmetic mean DPV concentration collected from the vaginal fluid near the site of the ring (blue), from the vaginal fluid on the surface of the cervix (red), the vaginal fluid on the surface of the introitus (purple) and the plasma (orange); patient data represents the mean values extracted was from Figure 2 of 21.
Figure 3
Figure 3
Dapivirine concentration–time profiles following administration of three vaginal rings (Group B dosing regimen in 21) measured in the vaginal fluid, plasma, epithelium tissue and stroma tissue. The first ring was inserted for 35 consecutive days and, upon removal, followed by a 3‐day period without a ring. The second ring was inserted for 21 days and on removal, a third ring was inserted immediately for 24 h. The black line represents the DPV concentration of a single patient simulated using the physiologically‐based pharmacokinetic parameters from Tables 1 and 2. The coloured lines represent the arithmetic mean DPV concentration collected from the vaginal fluid near the site of the ring (blue), from the vaginal fluid on the surface of the cervix (red), the vaginal fluid on the surface of the introitus (purple) and the plasma (orange); patient data represents the mean values extracted was from Figure 2 of 21. The individual panels show the DPV concentration in: (A) vaginal luminal fluid; (B) plasma; (C) vaginal epithelial tissue; and (D) vaginal stromal tissue
Figure 4
Figure 4
Dapivirine (DPV) concentration–time profiles following administration of a single vaginal film measured in the vaginal fluid, plasma, epithelium tissue and stroma tissue. The black line represents the DPV concentration of a single patient simulated using the physiologically‐based pharmacokinetic parameters from Tables 1 and 2. The coloured dots represent single time point measurements in patients participating in the FAME 02 study; DPV concentration was determined in the vaginal fluid (blue), plasma (orange), cervical tissue (red) and vaginal tissue (purple) for each patient in the hours following administration of dose 7. As the study did not provide information on the proportion of epithelium or stroma tissue present in their tissue samples, we include both vaginal and cervical tissue measurements on the plot. The individual panels show the DPV concentration in: (A) vaginal luminal fluid; (B) plasma; (C) vaginal epithelial tissue; and (D) vaginal stromal tissue
Figure 5
Figure 5
Dapivirine concentration–time profiles as for Figure 2 but including variability to allow for visual predictive check of simulated profiles. The visual predictive check simulations were run 1000 times for 30 patients with variability incorporated in to all model parameters using the values and associated coefficients of variation given in Tables 1 and 2. In each panel, the grey bands represent the variability in the 5th, 50th and 95th centiles while the black line shows the 50th centile value for each distribution
Figure 6
Figure 6
Dapivirine concentration–time profiles as for Figure 3 but including variability to allow for visual predictive check of simulated profiles. The visual predictive check simulations were run 1000 times for 30 patients with variability incorporated in to all model parameters using the values and associated coefficients of variation given in Tables 1 and 2. In each panel, the grey bands represent the variability in the 5th, 50th and 95th centiles while the black line shows the 50th centile value for each distribution
Figure 7
Figure 7
Dapivirine concentration–time profiles as for Figure 4 but including variability to allow for visual predictive check of simulated profiles. The visual predictive check simulations were run 1000 times for 30 patients with variability incorporated in to all model parameters using the values and associated coefficients of variation given in Table 1 and Table 2. In each panel, the grey bands represent the variability in the 5th, 50th and 95th centiles while the black line shows the 50th centile value for each distribution
Figure 8
Figure 8
The dapivirine (DPV) concentration–time profiles following insertion of a single vaginal ring for 28 consecutive days measured in the (A) vaginal fluid and (B) plasma. The black line represents the DPV concentration of a single patient simulated using the physiologically‐based pharmacokinetic parameters from Table 1 and Table 2. The coloured lines represent the average DPV concentration collected from patients the vaginal fluid near the site of the ring (blue), from the vaginal fluid on the surface of the cervix (red), the vaginal fluid on the surface of the introitus (purple) and the plasma (orange). The grey and orange bands (panels A and B, respectively) show the range of the patient data error bars extracted from Figure 1 of 23. Note that the original publication 23 does not report whether the data plotted represent the population mean and standard deviation or median and range
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