FormalPara Key Points

The physiologically based pharmacokinetic model in this study predicted that the transdermal delivery of islatravir through microneedle array patches ≤ 20 cm2 was able to achieve plasma concentrations above the minimum target 3, 6 and 12 months after administration with doses ranging from 15 mg to 80 mg.

Our study provides rationale for the further investigation of islatravir as a candidate for microneedle array patch administration.

1 Introduction

In 2020, there were approximately 37.7 million people living with HIV (PLWH) globally, with an estimated 74% receiving antiretroviral therapy (ART) [1]. ART currently consists of two- or three-drug regimens containing orally administered antiretrovirals (ARVs). ARVs can also be utilised for pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) in HIV-negative individuals encountering high-risk HIV exposures [2, 3]. ARVs target the HIV life cycle process both before and after HIV infiltration of the host cell, whilst some ARVs act as pharmacokinetic enhancers to enable effective therapeutic plasma concentrations [4,5,6]. Several ARVs are currently available for prevention and treatment. New ARVs are also in development to attain high potency while minimising the toxicity and drug interaction profile [7]. Moreover, long-acting ARVs are of increasing interest, with the notion being to reduce pill burden and issues surrounding drug adherence which are currently barriers to ART uptake and effectiveness [8, 9]. Additionally, several patient surveys have found high rates of interest in long-acting alternatives for HIV treatment and prevention [9]. To address these gaps in ART delivery and adherence, Cabenuva, which is a combination of cabotegravir (CAB) and rilpivirine (RPV) administered intramuscularly (IM), was approved by the FDA for the treatment of HIV in January 2021. Cabenuva is effective for once-monthly administration with studies indicating potential for administration every 2 months [10, 11]. However, alternative administration strategies remain of interest due to the disadvantages of IM formulations, including the need for administration by a skilled health worker, logistical challenges surrounding frequent clinic visits and resulting stigma [8, 9].

Microneedle array patches (MAPs) are a pain-free and discreet administration technique that consist of micron-scale needles capable of long-acting transdermal nanoparticulate drug delivery. MAP technologies have received increasing research efforts in the recent past, with their application extending beyond ART [12]. MAPs could help overcome the adherence issues surrounding oral administration whilst providing a potentially favourable administration route to IM injection for long-acting prevention and treatment of HIV. Drugs suitable for MAP delivery are characterised as highly potent with a long half-life, resulting in low doses capable of sustaining effective plasma concentrations over extended periods of time whilst maintaining appropriate MAP sizes [9, 13,14,15,16]. Islatravir (ISL) is a highly potent nucleoside reverse transcriptase translocation inhibitor with a long half-life that is currently being evaluated across multiple clinical trials for the prevention and treatment of HIV [17,18,19,20,21,22]. ISL prevents HIV replication through several unique mechanisms that are distinct from other nucleoside reverse transcriptase inhibitors [20, 23]. ISL enters peripheral blood mononuclear cells (PBMCs) where it undergoes rapid conversion via endogenous intracellular kinases to its active form, ISL-triphosphate (ISL-TP), before slowly converting back to ISL and re-entering the systemic circulation [24]. ISL has demonstrated a favourable long-acting profile, highlighting its potential for an extended duration of protection through MAP delivery [17, 20, 25].

Physiologically based pharmacokinetic (PBPK) modelling is an in silico technique that uses mathematical equations to describe the ADME processes and physiological characteristics of the human body as well as various species such as rats. Virtual cohorts of patients can be simulated for the prediction of drug pharmacokinetics resulting from numerous routes of administration and regimens by incorporating drug-specific physicochemical properties [26]. PBPK modelling can be employed for the investigation of ISL MAPs for ART by predicting clinical outcomes and highlighting MAP design requirements. A MAP intradermal PBPK model was previously reported and describes the movement of the drug through the stratum corneum, viable epidermis, and dermis whilst considering specific MAP characteristics [27]. The model was adapted and modified from a dermal PBPK modelling study that found that by considering skin sub-compartments and hair follicles, more accurate predictions could be made versus models with simpler structures [28]. The MAP intradermal PBPK model was successfully developed utilising rat in vivo data for nanoparticulate CAB and RPV and was applied for the prediction of CAB and RPV MAPs in humans [27].

The aim of this study was to develop and verify a whole-body PBPK model describing the conversion of ISL to ISL-TP for the prediction of ISL MAP pharmacokinetics. The study aimed to provide preliminary data to identify optimal dosing strategies, nanoparticle release rates and resulting MAP characteristics capable of sustaining effective ISL-TP concentrations to aid in future ISL MAP research initiatives.

2 Methods

A PBPK model was developed for ISL in Simbiology v5.8, a product of Matlab 2018a (MathWorks, Natick, MA, USA). Drug distribution in the intradermal MAP compartments was described using permeability-limited, first-order kinetics. The drug distribution in the remaining whole-body PBPK model was described using blood-flow-limited, first-order kinetics with well-stirred compartments that assumed instant distribution of the drug. Furthermore, it was assumed that there was no absorption of orally dosed drug from the large intestine. Physicochemical, pharmacokinetic, in vitro, and in vivo data for ISL and ISL-TP were sourced from the literature or, if unavailable, were estimated via curve fitting to the observed clinical data. Where applicable, concentration–time profile data were extracted from graphs using the Plot Digitizer Tool v4.5 (WebPlotDigitizer, Pacifica, California, USA). The PBPK model was verified against observed clinical data for both ISL and ISL-TP. Specifically, clinical data for ISL 0.5–30 mg single oral dose and ISL 60 mg and 120 mg once-monthly oral dose regimens were used. For model verification and application, virtual cohorts consisting of 50 male and 50 female patients aged 18–60 years were simulated.

2.1 Whole-Body PBPK Model

Weight and body mass index for virtual male and female patients aged 18–60 years were defined using data from the National Center for Health Statistics [29] and used to determine height and body surface area [30, 31]. These characteristics were applied in anthropometry equations to calculate organ weight [30], with organ density being implemented alongside weight to determine organ volume [32]. Furthermore, blood flow rates were defined as a fraction of the total cardiac output [33]. A multi-compartment absorption and transit model was implemented for the simulation of oral absorption [26, 34, 35]. Volume of distribution was calculated as previously described, with the zwitterionic olive oil:buffer partition coefficient (logD*vo:w) equation being applied for ISL [36]. The systemic circulation of ISL was calculated through previously reported differential equations for eliminating and non-eliminating organs [34]. A schematic representation of the whole-body PBPK model, including the MAP and PBMC compartments, can be found in Fig. 1 [37]. The physicochemical and pharmacokinetic input parameters for the simulation of ISL in the PBPK model are shown in Table 1. To note: the blood-to-plasma ratio (R) of ISL was calculated using Eqs. 1–4 in the Supplementary Material due to a lack of available data [38].

Fig. 1
figure 1

Schematic diagram of the whole-body PBPK model used to predict ISL and ISL-TP pharmacokinetics after oral administration. Organs, tissues, PBMCs and the MAP are represented by compartments, with the drug distribution represented by arrowed lines. Veins, arteries and their associated reactions are highlighted in blue and red, respectively, with reactions involved in absorption, metabolism and excretion highlighted in yellow. Compartments and reactions involved in first-pass metabolism are located within the grey box, with those involved in systemic circulation enclosed within the dashed line. PBPK physiologically based pharmacokinetic modelling, ISL islatravir, ISL-TP islatravir triphosphate, PBMCs peripheral blood mononuclear cells, MAP microneedle array patch

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Table 1 Physicochemical and pharmacokinetic input parameters for the ISL PBPK model
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The conversion pathway of ISL to ISL-TP [24] was integrated into the whole-body PBPK model using Eqs. 1–3, with a schematic representation being shown in Fig. 2. Avein,ISL, APBMC,ISL,in and APBMC,ISL,out are the amounts of ISL in the vein compartment, entering the PBMC compartment, and leaving the PBMC compartment, respectively. APBMC,ISLTP is the amount of ISL-TP in the PBMC compartment. Kin,ISL and Kout,ISL are the rates at which ISL enters and leaves the PBMC compartment, respectively. KISL,ISLTP and KISLTP,ISL are the rates of ISL conversion to ISL-TP and ISL-TP conversion to ISL, respectively. Due to a lack of data, Kin,ISL, Kout,ISL, KISL,ISLTP and KISLTP,ISL were estimated via curve fitting. This process was carried out in a stepwise manner whereby initial values for each parameter were selected based on the rapid conversion of ISL to ISL-TP and slow return of ISL-TP to ISL within PBMCs, as outlined in the literature [24]. Each value was optimised incrementally until the ratio of predicted vs observed and the absolute average fold error (AAFE) values for the 0.5–30 mg oral regimens fell within the verification criteria [17]. The optimised values underwent secondary verification through the simulation of the 60 mg and 120 mg oral once-monthly ISL regimens [22]. Additionally, 1.17 × 109 PBMCs per litre of blood were considered in the PBPK model [44].

Fig. 2
figure 2

PBMC compartment structure describing the conversion pathway of ISL to ISL-TP integrated with the vein compartment of the whole-body PBPK model. PBMC peripheral blood mononuclear cells. Avein,ISL, APBMC,ISL,in, APBMC,ISL,out amounts of ISL in the vein compartment, entering the PBMC compartment and leaving the PBMC compartment, respectively; APBMC,ISLTP amount of ISL-TP in the PBMC compartment; Kin,ISL, Kout,ISL rates at which ISL enters and leaves the PBMC compartment, respectively; KISL,ISLTP, KISLTP,ISL rates of ISL conversion to ISL-TP and ISL-TP conversion to ISL, respectively

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$$\frac{{\text{d}}{{A}}_{\text{PBMC,ISL,in}}}{{\text{d}}{{t}}} = {{K}}_{\text{in,ISL}} \times {{A}}_{\text{vein,ISL}} \, - \, {{K}}_{\text{ISL,ISLTP}} \times {{A}}_{\text{PBMC,ISL,in}}$$
(1)
$$\frac{{\text{d}}{{A}}_{\text{PBMC,ISLTP}}}{{\text{d}}{{t}}} = {{K}}_{\text{ISL,ISLTP}}\times {{A}}_{\text{PBMC,ISL,in}} - {{K}}_{\text{ISLTP,ISL}} \times {{A}}_{\text{PBMC,ISLTP}}$$
(2)
$$\frac{{\text{d}}{A}_{\text{PBMC,ISL,out}}} {{{\text{d}}{t}}}= {{K}}_{\text{ISLTP,ISL}} \times {{A}}_{\text{PBMC,ISLTP}} - {{K}}_{\text{out,ISL}} \times {{A}}_{\text{PBMC,ISL,out}}.$$
(3)

2.2 MAP Intradermal PBPK Model

The MAP intradermal PBPK model was previously described, with a schematic representation being shown in Fig. 3 [27]. Due to limited data, the MAP formulation dose loading of 4.09 mg/cm2 applied for CAB and RPV was also used for ISL. The partition coefficient and permeability coefficient input parameters describing the movement of ISL throughout the skin layers were calculated using the average value from collated quantitative structure–property relationship (QSPR) equations [27, 28]. The partition coefficient and permeability coefficient input parameters for ISL are shown in Table 2. Similarly to the previously described MAP intradermal PBPK model, the rate of transfer of free drug between skin layers was assumed to be 1 h−1 [27].

Fig. 3
figure 3

Schematic representation of the drug release pathway implemented in the MAP intradermal PBPK model. Diagram adapted from Rajoli et al. [27]

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Table 2 Calculated partition coefficient and permeability coefficient input parameters for the ISL MAP intradermal PBPK model [27]
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2.3 PBPK Model Verification

The reported MAP intradermal PBPK model utilised in this study was previously verified. Briefly, the PBPK model was successfully verified against CAB and RPV rat and human intramuscular injection pharmacokinetic data alongside intradermal MAP pharmacokinetic data in rats [27]. Moreover, the whole-body PBPK model with the integrated ISL to ISL-TP conversion mechanism developed herein was considered successfully verified if the ratio of predicted vs observed pharmacokinetic values for orally administered ISL and ISL-TP was between 0.5-fold and 2-fold [45]. In addition, the absolute average fold error (AAFE) for the predicted vs observed pharmacokinetic parameters and concentration–time profiles were also calculated, as defined in Eq. 4, where N is the number of data points [46]. AAFE values between 1 and 2 were considered successfully verified.

$${\rm AAFE}={10}^{\left|\frac{1}{{{N}}}\Sigma {\text{log}}\frac{\text{Predicted}}{{\text{Observed}}}\right|}$$
(4)

2.4 Prediction of Islatravir MAP Pharmacokinetics

Dosing strategies for ISL MAP simulations were based upon a maximum therapeutic area of 20 cm2 (assuming a dose loading of 4.09 mg/cm2 [27]), a minimum ISL-TP target concentration of 0.05 pmol/106 PBMCs [22] and a minimum duration of 3 months. Simulations aimed to determine the maximum dosing interval achievable under these criteria. To provide an overview of potential clinical scenarios, nanoparticle release rates of 0.005 h−1, 0.0025 h−1 and 0.0005 h−1 were simulated based upon the previously reported MAP intradermal PBPK model study [27]. Additionally, due to the lack of data, a range of bioavailability scenarios which account for MAP delivery efficiency and movement of ISL from the skin into systemic circulation from 25 to 100% were simulated for each MAP dose.

3 Results

3.1 PBPK Model Verification

The PBPK model was successfully verified according to the criteria by comparing the predicted area under the curve (AUC), maximum concentration (Cmax), concentration at 168 h (C168), and concentration–time profiles with the observed clinical data for the oral administration of ISL and its product ISL-TP. The AAFE and ratio verification results for the predicted ISL and ISL-TP pharmacokinetics from single-dose oral ISL regimens can be found in Tables 3 and 4, respectively [17]. The predicted concentration–time profiles of ISL-TP resulting from single-dose oral ISL regimens can be found in Figs. 1–5 of the Supplementary Material. The predicted concentration time profiles of ISL-TP resulting from once-monthly 60 mg and 120 mg oral doses of ISL can be found in Figs. 4 and 5, respectively [22]. The parameters applied in the model to describe the conversion of ISL to ISL-TP were estimated via curve fitting to the observed clinical data.

Table 3 Predicted vs observed ISL pharmacokinetics following single-dose oral administration [17]
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Table 4 Predicted vs observed ISL-TP pharmacokinetics following single-dose oral administration of ISL [17]
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Fig. 4
figure 4

Observed vs predicted concentration–time profile of ISL-TP after once-monthly oral administration of 60 mg ISL. The red circles represent the mean of the observed clinical data (pmol/106 PBMCs) of ~ 100 HIV negative people [22]. The blue line represents the mean (pmol/106 PBMCs) of the predicted data. The green dashed line represents the minimum target concentration of 0.05 pmol/106 PBMCs [22]

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Fig. 5
figure 5

Observed vs predicted concentration–time profile of ISL-TP after once-monthly oral administration of 120 mg ISL. The red circles represent the mean of the observed clinical data (pmol/106 PBMCs) of ~ 100 HIV negative people [22]. The blue line represents the mean (pmol/106 PBMCs) of the predicted data. The green dashed line represents the minimum target concentration of 0.05 pmol/106 PBMCs [22]

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Parameters Kin,ISL, KISL,ISLTP, KISLTP,ISL and Kout,ISL were estimated as 4 h−1, 4 h−1, 0.006 h−1 and 1 h−1, respectively, via curve fitting to the available clinical data. Furthermore, the equation calculating Ka [34] was unable to accurately describe the absorption of oral ISL, and so this value was also estimated via curve fitting to equal 1.5 h−1.

3.2 Predicted ISL MAP Pharmacokinetics

The MAP intradermal PBPK model was integrated into the verified ISL PBPK model for the simulation of ISL MAPs. Release rates of 0.005 h−1, 0.0025 h−1 and 0.0005 h−1 were considered alongside ISL MAP bioavailability ranging from 25 to 100% to provide an overview of potential clinical scenarios. A maximum therapeutic area of 20 cm2 (4.09 mg/cm2 dose loading) and a minimum ISL-TP concentration of 0.05 pmol/106 PBMCs was targeted during MAP dosing simulations. The predicted ISL-TP Cmin at 3, 6 and 12 months after the administration of 15 mg (3.67 cm2), 30 mg (7.34 cm2), 60 mg (14.68 cm2) and 80 mg (19.57 cm2) ISL MAPs can be found in Tables 5, 6, 7 and 8, respectively.

Table 5 Predicted Cmin pharmacokinetics of 15 mg ISL MAPs 3, 6 and 12 months after administration
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Table 6 Predicted Cmin pharmacokinetics of 30 mg ISL MAPs 3, 6 and 12 months after administration
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Table 7 Predicted Cmin pharmacokinetics of 60 mg ISL MAPs 3, 6 and 12 months after administration
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Table 8 Predicted Cmin pharmacokinetics of 80 mg ISL MAPs 3, 6 and 12 months after administration
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All ISL MAP dosing regimens simulated across all bioavailability percentages with a release rate of 0.0005 h−1 achieved the minimum target concentration 3 months after administration. MAP dosing of 30 mg, 60 mg, and 80 mg sustained concentrations above the minimum target at 3 months with a release rate of 0.0025 h−1, although only the 80 mg dose was able to achieve this across all bioavailability scenarios. Similarly, all ISL MAP dosing regimens were able to achieve the minimum target concentration 6 months after administration with a release rate of 0.0005 h−1. However, 15 mg and 30 mg MAP dosing were only able to attain this with select bioavailability rates (15 mg: 75%, 100%; 30 mg: 50%, 75%, 100%). Dosing regimens with a release rate of 0.0025 h−1 did not achieve the minimum target concentration across any bioavailability scenario 6 and 12 months after administration. The simulated 80 mg ISL MAP sustained ISL-TP concentrations above the minimum target concentration up to 12 months after administration with a release rate of 0.0005 h−1 and a bioavailability of 100%. MAPs with a release rate of 0.005 h−1 did not achieve the minimum target concentration of ISL-TP for any dosing regimen at 3, 6 or 12 months after administration. Additionally, the time taken to reach the minimum target concentration after MAP administration increased with slower release rates, lower doses, and lower bioavailability. A maximum time of approximately 5 days was predicted to reach the minimum target concentration for the 15 mg ISL MAP with a bioavailability of 25% and release rate of 0.0005 h−1.

4 Discussion

ISL is a potent ARV with promising characteristics for long-acting technologies [20]. Specifically, nanoparticulate ISL MAPs have the potential to provide pain-free and discreet long-acting administration for the prevention and treatment of HIV. In this study, the conversion of ISL to its active form, ISL-TP, was mathematically described and implemented in a MAP intradermal PBPK model [27]. Cohorts of virtual patients were simulated to predict optimal MAP dosing strategies and nanoparticle release rates to sustain effective ISL-TP concentrations over extended periods of time.

The PBPK model describing the conversion of ISL to ISL-TP was successfully verified against multiple data sets for the oral single-dose ISL administration. There was a general trend for the PBPK model to underpredict the ISL-TP pharmacokinetics for 0.5 mg and 1 mg doses and overpredict the ISL-TP pharmacokinetics for 2 mg, 10 mg and 30 mg doses, as shown in Tables 3 and 4 and Figs. 1–5 in the Supplementary Material. These trends, alongside the available clinical data, suggest that the pharmacokinetics of ISL-TP are not necessarily dose proportional, contrary to what was previously reported [17]. However, the small patient sample size (n = 6) for the available oral single-dose ISL clinical data must be taken into consideration when analysing the verification data [17]. A larger sample size would be required to definitively assess whether ISL-TP pharmacokinetics are dose proportional before PBPK modelling strategies to describe non-linear drug pharmacokinetics could be justifiably implemented. Furthermore, due to the recent development of ISL, clinical pharmacokinetic data are scarce, and future PBPK modelling initiatives utilising emerging ISL clinical data will be essential for refining prediction accuracy. For example, the available apparent permeability data for ISL [41] was unable to accurately predict ISL absorption using the equation for Ka in the model [34]. A previous study found that drugs with an effective permeability of lower than 1 × 10−4 cm/s (ISL Papp = 6.265 × 10−7 cm/s) showed a wide range of fraction absorbed values, leading to techniques such as Caco-2 cell permeability proving unreliable in some instances. Under these circumstances, it is justifiable to utilise alternative means to calculate the fraction absorbed, hence the estimation of Ka in this study in the absence of alternative Papp data. In addition to the single-dose ISL clinical data, the PBPK model was successfully verified against clinical data for 60 mg and 120 mg once-monthly oral ISL administration [22]. Although these data sets were limited to the concentration–time profile alone, their likeness to the extended dosing intervals simulated for the ISL MAP regimens aids in model reliability.

The employed mechanism and estimated parameters describing the conversion of ISL to ISL-TP proved successful in simulating the ISL and ISL-TP pharmacokinetics. The mechanism was based on the uptake of ISL into PBMCs (Kin,ISL), where it then underwent rapid conversion via endogenous intracellular kinases to ISL-TP (KISL,ISLTP), before slowly converting back to ISL (KISLTP,ISL), followed by efflux out of the PBMCs (Kout,ISL) [24]. However, due to a lack of data, the parameters applied to describe this process were estimated and present a limitation of the current model, especially considering the limited availability of clinical data available for model verification. This current limitation could be resolved through the generation of in vitro and in vivo data describing the outlined parameters. Specifically, the concentration of ISL within PBMCs would provide us with additional confidence in parameter estimation, although this may be challenging to determine in vitro due to its rapid conversion to ISL-TP.

The ISL whole-body PBPK model integrated with the MAP intradermal PBPK model was used to predict the ISL and ISL-TP pharmacokinetics resulting from varying MAP design strategies to determine the long-acting administration potential of ISL. With the maximum therapeutic area of 20 cm2 and dose loading of 4.09 mg/cm2 [27] being the major limiting factors for MAP design in this study, the PBPK model predicted that doses of between 15 and 80 mg could sustain ISL-TP concentrations above the minimum target concentration over 3–12 months. Nanoparticle release rate and MAP bioavailability had a significant impact on the administration timeframe, whereby faster nanoparticle release rates and a lower bioavailability decreased the period of time that ISL-TP concentrations were greater than 0.05 pmol/106 PBMCs. As these two aspects of ISL MAPs are currently unknown, several scenarios were simulated to obtain a wider understanding of potential clinical outcomes and outline target characteristics for future MAP designs capable of long-acting administration; however, questions surrounding the practicality of these characteristics for ISL MAPs remain unanswered. Unlike the previously reported MAP intradermal PBPK model for CAB and RPV [27], the model applied herein was not verified against in vivo ISL MAP data due to its lack of availability, and this presents as a limitation of this study. Future in vitro and in vivo studies could fill the knowledge gap for various ISL MAP intradermal PBPK modelling, enabling more reliable predictions of clinical outcomes. Nonetheless, the ISL MAP simulations presented in this study provide insightful preliminary data for the investigation of ISL as a MAP candidate.

As mentioned, the dose loading implemented for the CAB and RPV MAP intradermal PBPK model [27] was applied in this study due to the lack of available data for ISL MAPs. The dose loading per cm2 of MAP has a direct impact on therapeutic area and overall MAP size, with higher amounts of drug per cm2 of MAP resulting in smaller sizes. If the currently simulated 4.09 mg/cm2 dose loading is unattainable for ISL MAPs, the maximum administration timeframe of 12 months could be reduced significantly. Conversely, if a dose loading greater than 4.09 mg/cm2 can be achieved, the maximum administration could increase beyond 12 months. MAP size is an important factor from both implementation and patient acceptability perspectives. Although larger MAPs can contain greater amounts of drug and benefit from extended durations of protection, they could present challenges when applying them to different body sites, reducing discreetness and ease of use [47]. In this study, although differing MAP therapeutic areas could be calculated based on alternative dose loadings, the pharmacokinetics for each dose simulated herein would not necessarily be reflective of those resulting from other dose loading scenarios. This is a result of two factors. Firstly, dose loading is not only affected by a drug’s physicochemical properties but also by the MAP design, such as microneedle shape and density [13, 14]. The MAP intradermal PBPK model contains mathematical descriptions of the specific MAP design to enable accurate simulation of drug movement throughout the skin layers to the systemic circulation. Therefore, the current model structure may not be able to account for alternative dose loadings that are the result of different MAP designs, reducing simulation accuracy and overall model reliability. Secondly, the current MAP intradermal PBPK model contains unknown parameters, of which CAB and RPV in vivo data from a specific MAP design with a dose loading of 4.09 mg/cm2 were used for parameter estimation. Additional model verification with different MAP designs would be required to verify that these estimated parameters are applicable across all MAP intradermal PBPK models.

Whilst ISL MAPs show potential for long-acting administration, their clinical application must be taken into consideration. ISL is currently being assessed for both the prevention and treatment of HIV [17,18,19,20,21,22, 24]. In the case of pre-exposure prophylaxis (PrEP), ISL is being assessed alone; however, for treatment, ISL is being assessed as a three-drug regimen alongside doravirine (DOR) and lamivudine (3TC) [17]. For HIV treatment via MAP delivery, pairing ISL with another highly potent ARV such as lenacapavir would also be advantageous. Future research initiatives could apply the PBPK model used in this study to assess potential candidates together with ISL as two- or three-drug regimens for the treatment of HIV via MAP delivery. Additionally, as predicted by the PBPK model, the time taken to achieve the minimum target concentration after administration increased with decreasing nanoparticle release rates, bioavailability and dose. For successful prevention and treatment of HIV, concentrations within the therapeutic window must be achieved as quickly as possible [48]. It may therefore be necessary to consider an oral lead in of ISL for certain MAP designs to sustain appropriate concentrations over a shorter period of time. Furthermore, consideration must be made of the pharmacokinetic tail of ISL MAPs, with appropriate measures being made during clinical management. Specifically, as with any pharmacokinetic tail in long-acting ARV technologies, concerns surround the potential for the emergence of resistant HIV strains after long-acting treatment cessation [49, 50]. That being said, in December 2021, Merck published a news release stating that the FDA had placed clinical holds and partial clinical holds on several ISL clinical trials due to reported decreases in CD4+ T cells and total lymphocytes amongst some participants in the studies [51]. Whilst no further updates on the clinical holds have currently been published, the utility of this study remains, as it provides preliminary data and guidance on the design and application of ISL MAPs for the treatment and prevention of HIV.

5 Conclusion

A mathematical description of the conversion of ISL to ISL-TP was successfully verified. The PBPK model predicted the pharmacokinetics of ISL and ISL-TP up to 12 months after MAP administration, highlighting key characteristics such as dose and nanoparticle release rate required to sustain concentrations above the minimum target concentration with a favourable MAP therapeutic area. Based on the simulated data, ISL MAP doses of 80 mg were found to be suitable for 12-month administration, whilst doses as low as 15 mg were suitable for 6-month administration. This in silico study provides rationale for further investigation of ISL as a candidate for MAP administration if holds on ISL clinical trials employed by the FDA are lifted.