Novel Bilayer Microarray Patch‐Assisted Long‐Acting Micro‐Depot Cabotegravir Intradermal Delivery for HIV Pre‐Exposure Prophylaxis

Novel Bilayer Microarray Patch‐Assisted Long‐Acting Micro‐Depot Cabotegravir Intradermal Delivery for HIV Pre‐Exposure Prophylaxis

The results from the in vitro and ex vivo characterization revealed that the finalized bilayer CAB-MAPs, namely CAB LA-MAP, CAB Na-MAP, and CAB FA-MAP, were promising, as they were stable, mechanically strong, and able to deliver substantial amounts of CAB into ex vivo skin. However, these findings need to be complemented by in vivo data to evaluate the performance (pharmacokinetics [PK]), safety, and tolerability of the finalized CAB-MAPs following single and repeated dosing using healthy female Sprague Dawley rats, a good preclinical model for screening and evaluating the PK of long-acting formulations.[63] For comparison, rats received the proprietary CAB LA nanosuspension by IM injection (the conventional administration route) or by ID injection (to evaluate the effect of the anatomy and physiology of the skin). Studies details were reported in (Section S8, Supporting Information).

To facilitate translating our in vivo findings to human application, while accounting for the biological and anatomical differences between humans and rats and the fact that rats eliminate drugs faster than humans,[64] allometric scaling (Section S9, Supporting Information) was used to calculate the monthly dose for rats based on a human monthly dose of 400 mg (equates to 5.71 mg/kg in a person with an average body weight of 70 kg).[13] This was found to be ≈40 mg/kg (equates to 10 mg/rat, for a rat with an average body weight of 250 g).[64]

2.6.1 CAB Pharmacokinetics After a Single Dose of CAB-MAPs

As the first step in MAP performance assessment, this study was designed i) to evaluate MAP’s functionality in vivo (the ability of the finalized CAB-MAP tips to be inserted in the skin, dissolved, and have deposited their payload); ii) to evaluate how the skin anatomy and physiology (where MAPs are expected to deliver their payload) would affect CAB PK in comparison with IM injection; iii) to estimate MAP delivery efficiency and absorption rate and assess whether the three drug-forms—namely CAB LA, CAB Na, or CAB FA—delivered by MAPs would achieve long-acting PK profiles that maintain drug plasma levels above the effective therapeutic concentration in humans over a 4-week period (to mimic human monthly dosing) in a similar fashion to IM injection (the conventional administration route). The effective therapeutic concentration in humans that provides 100% protection against HIV-1 was reported to be 0.664 µg mL−1, which is equivalent to four times the protein-adjusted 90% inhibitory concentration (4 × PA-IC90).[65]

To this end, five cohorts of rats were assigned to this study, as illustrated in Figure 5A. In the first two cohorts, each rat received CAB LA (10 mg/rat) by either IM injection (cohort 1) or ID injection (cohort 2). The other three cohorts (3–5) were allocated for MAP application. In these three cohorts, each rat received the drug by simultaneous application of 4× MAPs of either the finalized CAB LA-MAP (cohort 3), CAB Na-MAP (cohort 4), or CAB FA-MAP (cohort 5) for 24 h. The skin at MAP application sites was imaged post MAPs remaining removal (after 24 h from the application) using a digital camera and inspected for evidence of drug delivery and any sign of toxicity or irritation (Figure 5B). Blood samples were collected from all cohorts at predetermined time intervals over 28 days (Figure 5C) and assayed for CAB content by a validated UPLC-MS-MS method (Figure 5D) (Section S10, Supporting Information). Data were then used to construct the mean CAB plasma concentration versus time profiles, which were then used to calculate the key PK parameters (Section S11, Supporting Information), including the maximum drug concentration (Cmax), the time of maximum concentration (Tmax), the apparent half-life (t0.5), and drug minimum concentration (Ctrough), that is, (C28) at day 28. The area-under-the-curve from time zero (t = 0) to the last experimental time point (t = 28 days) (AUC0–28) and the dose/body weight normalized PK parameters (specifically Cmax and AUC0–28) (Table 1) were used for comparison with their corresponding PK parameters achieved by administering the drug by IM injection. Finally, the relative bioavailability (FR) in comparison with IM injection was also calculated and reported. Furthermore, conducting such a comprehensive study necessitated using a considerable number of rats and performing the experiment in multiple steps, which resulted in inevitable inter-cohort weight variations. Due to the difficulty of tailoring the administered dose as per rats’ weights, a fixed dose (assuming a rat’s average weight to be ≈250 g) was given to each rat as per cohort, which resulted in inter-cohort dose/body weight (calculated as mg/kg) disparity. To eliminate the effect of the inter-cohort dose/body weight (mg/kg) disparity among the cohorts of interest, weight-dependent PK parameters, specifically drug concentrations (C) and the area-under-the-curve (AUC), were normalized (Section S11, Supporting Information) and reported.

A) Schematic representation of the in vivo experimental setup [* For single dose, three cohorts were allocated to receive the drug by simultaneous application of 4× patches of either the finalized CAB LA-MAP, CAB Na-MAP, or CAB FA-MAP. For repeated dose, two cohorts were allocated to receive the drug by simultaneous application of either 4× patches or 2× patches of the finalized CAB LA-MAP]. B) Exemplar digital images of rat skin at the application site upon removal of CAB LA-MAP post-24 h application with visible whitish micro-depots representing MAP tips implanted in the skin. C) Schematic diagram representing blood collection from rats at predetermined time intervals over studies periods. D) Schematic illustration of LC-MS setup used. E) CAB PK profiles post administration of a single dose of CAB LA either by IM injection or ID injection or applying 4× CAB LA-MAP (containing ≈11.72 mg CAB LA in total), 4× CAB Na-MAP (containing ≈11.0 mg CAB Na in total), or 4× CAB FA-MAP (containing ≈11.8 mg CAB FA in total). F) CAB PK profiles post administration of a repeated once-weekly × 4 doses of CAB LA (2.5 mg/rat) by IM injection or ID injection or applying 4× or 2× CAB LA-MAP (containing 11.72 or 5.86 mg in total, respectively). Red dotted lines in (E) and (F) indicate the minimum therapeutic plasma levels for PrEP (4× PA-IC90 = 0.664 µg mL−1). Data are reported as means ± SD, n ≥ 5.

Table 1.
CAB PK parameters in Sprague Dawley rats and their corresponding dose/body weight-normalized counterparts following administration a single dose of either CAB LA, CAB Na, or CAB FA by either IM or ID injection or MAP application. Data are reported as mean ± SD, n ≥ 5
Experimental PK parameters Dose/body weight (as if 40 mg/kg is given) normalized PK parameters
Cohort no. Drug form used/admin. route Dose[mg/kg] Tmax[days] t0.5[days] Cmax[µg mL−1] AUC0–28[µg.day mL−1] C28[µg mL−1] norm-Cmax[µg mL−1] norm-AUC0–28[µg.day mL−1]
1 CAB LA/IM 35.9 (±4.5) 9

67.1

(±7.6)

1472.5

(±150.0)

67.1

(±9.1)

74.7

(±8.6)

1637.6

(±167.2)

2 CAB LA/ID

50.2

(±4.0)

14

71.9

(±10.4)

1459.8

(±324.2)

69.4

(±15.8)

57.3

(±8.3)

1163.2

(±258.3)

3 CAB LA-MAP

35.3

(±2.4)

5 7.3

18.1

(±2.3)

291.1

(±23.4)

3.1

(±1.1)

20.5

(±2.6)

329.8

(±26.5)

4 CAB Na-MAP

59.3

(±1.8)

6 5.8

39.3

(±5.8)

454.3

(±23.4)

2.7

(±0.4)

26.5

(±3.9)

306.5

(±15.8)

5 CAB FA-MAP

61.0

(±2.1)

6 4.5

18.7

(±3.2)

226.3

(±13.4)

0.9

(±0.7)

12.4

(±2.1)

148.4

(±8.8)

Inspecting skin at application sites (Figure 5B) in all rats (cohorts 3–5) showed that, post-application for 24 h, all MAPs completely dissolved, forming a whitish gluey mass consisted of the undelivered drug and the dissolved polymers from the baseplates (images are not shown). After a meticulous cleaning, hundreds of whitish microdots were revealed to be deposited in the skin (Figure 5B), which comprised the implanted MAP drug-loaded tips in the skin. This observation was consistent with the findings of ex vivo drug deposition studies reported in the previous section, confirming the functionality of the finalized CAB-MAPs in an in vivo setup.

Regarding the effect of skin anatomy and physiology of CAB PK in comparison with IM injection, we studied the CAB PK profiles produced by ID injection and compared them to those produced by IM injection. In those rats that received CAB LA by IM injection, the drug appeared in plasma within 1 h (the first sampling point) post-dosing and rapidly increased in concentration to reach ≈8.4 µg mL−1 at 4 h and then continued to increase gradually to reach its Cmax (67.1 µg mL−1) at Tmax (9 days). Subsequently, drug concentrations continued fluctuating around Cmax until day 28 (the end of the study period). This PK profile and parameters are very comparable to a previously reported CAB LA PK profile, where it was previously reported that Tmax = 7–14 days and Cmax ≈ 70.5 µg mL−1 upon administering a similar CAB LA dose (40 mg/kg) by IM injection to the same strain of rats.[66] In those rats that received CAB LA by ID injection, the drug exhibited almost identical PK profiles, except the time (Tmax = 14 days) to reach Cmax (71.0 µg mL−1). This time is significantly (p < 0.05) longer than that observed post IM injection. Upon comparing the normalized PK parameters (Table 1), specifically the norm-Cmax (≈57.3 µg mL−1), and norm-AUC0–28 (≈1163.2 µg.day mL−1), were found to be significantly lower (p < 0.05) and equate to ≈76.6 and ≈71.0%, respectively, of the corresponding PK parameters produced by IM injection (≈74.7 µg mL−1 and ≈1637.6 µg.day mL−1, respectively). Taking into consideration that ID-injected drug by the hypodermic needle can be completely delivered into the skin, it concluded that the longer Tmax, and lower norm-Cmax and norm-AUC0–28, were not because of the decreased delivery efficiency but may be due to a decreased dissolution or absorption rate from the viable skin layers. This was not unexpected, taking into account the inherited structural physiological differences between the two tissues and the slower blood flow rate in the skin tissue, in comparison with blood flow in the muscles.[67] Interestingly, the PK profile of CAB post ID injection of CAB LA presented here was comparable to CAB PK profiles obtained post administering an equivalent dose of CAB LA to rats of the same strain by subcutaneous injection.[66]

The PK profiles of CAB in the rats from the three cohorts (3–5) that received the three forms of the drug by MAPs (Figure 5E), showed that, similarly to IM injection, the drug appeared in plasma within 1 h of dosing and no lag time was observed. CAB plasma concentration then increased rapidly to achieve plasma levels 2.8-fold above 4× PA-IC90 after 4 h from dosing and continued increasing to achieve Cmax at Tmax (5 days for CAB LA-MAP and 6 days for the other two MAPs), indicating fast absorption rates from MAPs. Subsequently, the plasma levels fluctuated around Cmax for a few days and then decreased gradually to reach (C28) at day 28, which was MAP type-dependent, but was still above 4× PA-IC90 in all three cohorts.

The observed Tmax (5 and 6 days) in those rats that received the drug by MAPs were significantly (p > 0.05) shorter than Tmax post IM injection (9 days) or ID injection (14 days). This suggests that the drug absorption rate from MAP application sites was greater than that from IM and ID injected depots. This may be ascribed to the hundreds of micro-depots the MAP drug-loaded tips implanted in the skin, which will have considerably larger surface areas than the single “large” depot delivered by IM or ID injection using hypodermic needles.[68] The higher absorption rate achieved by MAPs has a potential advantage, not only because it combats the slower absorption rate caused by the inherited physiology and anatomy of the skin, but also because it could help in quickly achieving the required drug plasma levels for immediate protection against HIV-1 infections.

In terms of MAP delivery efficiency, CAB plasma exposure (as exemplified by Cmax and AUC0–28) achieved by all CAB-MAPs were MAP type-dependent and significantly lower than that achieved by IM injection (Table 1), which is consistent with incomplete drug delivery by MAPs. This was not unexpected for such a hydrophobic drug, and indeed, it was in good agreement with our observation of the skin at MAP application sites (in vivo) and with the results of the ex vivo drug deposition studies reported in the previous section. Accordingly, not all drugs encapsulated within the MAP tips would be expected to be delivered throughout the 24 h application time, unlike the complete delivery by IM or ID injection.

At this stage, it was very challenging to accurately calculate the relative bioavailability (FR) of the drug from MAPs in comparison with IM injection due to incomplete drug absorption from both IM and MAP cohorts over 28 days (the study period). However, assuming no significant differences in the drug absorption and elimination kinetics between the two administration routes, IM, or MAP, from day 28 and onward, we can still cautiously use the partial absorption data to calculate FR and then use it to perform estimation for the percentage of drug delivered by each MAP. Under this assumption, the FR of drugs from CAB LA-MAP, CAB Na-MAP, and CAB FA-MAP were of the magnitude 0.2, 0.19, and 0.09, respectively. Hence, the amount of drug delivered by 4× MAPs/rat would be of the magnitude of ≈0.585 mg/MAP × 4 ≈2.340 mg for CAB LA-MAP, ≈0.570 mg/MAP × 4 ≈2.280 mg for CAB Na-MAP, and ≈0.270 mg/MAP × 4 ≈1.080 mg for CAB FA-MAP, respectively. This suggests that both CAB LA-MAP and CAB Na-MAP exhibited a comparable relative bioavailability that was almost twice that achieved by CAB FA-MAP. This finding is consistent with in vivo observation and in good agreement with the results of the ex vivo drug deposition study reported in the previous section.

Interestingly, despite the incomplete drug delivery by MAPs, the delivered doses rapidly achieved plasma levels that were maintained above 4× PA-IC90 throughout the 28-day study period, indicating long-acting PK profiles achieved by the applied CAB-MAPs. This was evident from the achieved (C28) at day 28 by CAB LA-MAP, CAB Na-MAP, and CAB FA-MAP, which were of the magnitude ≈3.1, ≈2.7, and ≈0.9 µg mL−1, respectively. These are ≈4.7, ≈4.1, and ≈1.4-fold, respectively, above the 4× PA-IC90.

The comparable C28 achieved by CAB LA-MAP and CAB Na-MAP, which are several-fold higher than that achieved by CAB FA-MAP, could be due to the relatively high delivery efficiency achieved by those two MAPs.

These findings are very encouraging and demonstrated the functionality of these MAPs in rats. However, in order to predict MAP performance in humans, the correlation between CAB delivered by MAPs and that delivered by IM injection (the conventional administration route) in terms of PK behavior should be investigated and then extrapolated to PK behavior in human post-administration by the same route (IM injection). This can be achieved by calculating the apparent half-life (t0.5) of CAB and using it for comparison.

Calculating t0.5 of CAB LA post-IM injection in rats using the PK profile produced upon injecting 10 mg/rat (equate to ≈40 mg/kg) was rather difficult, since the drug reached Cmax and remained around that concentration until the end of the study. Therefore, lower doses of CAB LA of either 5 mg/rat (equates to 21.3 mg/kg) or 2.5 mg/rat (equates to 10.4 mg/kg) (Section S12, Supporting Information) were used to calculate t0.5 and investigate the effect of the administered dose on t0.5. This study showed that t0.5 of CAB post-administration of CAB LA by IM injection was dose-dependent and was in the magnitude of 12.3 days (for dose of 5 mg/rat) and 9.0 days (for dose of 2.5 mg/rat), respectively (Section S12, Supporting Information). This suggests that CAB follows “flip flop” pharmacokinetics,[69] which means that drug persistence in the body central compartment (plasma exposure), and thus its apparent t0.5, is dependent upon the absorption process, rather than the drug elimination process. Thus, the higher delivered dose and the slower the absorption rate, the longer the apparent t0.5.[69]

Taking into consideration that the administered CAB LA dose of 2.5 mg/rat (equates to 10.4 mg/kg) is closely related to the CAB LA dose of 800 mg (≈11.4 mg/kg) in humans without allometric scaling,[13] the apparent t0.5 (≈9.0 days) of CAB in rats is ≈4.4-fold shorter than that (≈40 days [25–54 days]) observed in humans post administering CAB LA by the same route. This is consistent with the fact that rats generally eliminate drugs at faster rates than humans.[64]

The apparent t0.5 of CAB achieved post-applying CAB LA-MAP and CAB Na-MAP were of the magnitude of ≈7.3 and ≈5.8 days, respectively. These are within the same range of that (≈9.0 day) achieved by CAB LA administered by IM injection and represent a duration 5.4- to 6.8-fold shorter than that (≈40 days) observed in humans post administering CAB LA by IM injection. This suggests it is most likely that, if either CAB LA or CAB Na were delivered by MAPs in a human, they would behave pharmacokinetically in a similar fashion to CAB LA delivered by IM injection.

The apparent t0.5 of CAB in rats, calculated here, is of great importance, as it can be also used to estimate the dosing interval (T) in rats that mimics the currently used dosing intervals in humans (monthly or bimonthly), providing that closely related doses are used, without allometric scaling. Currently, in the monthly dosing regimen in humans, the T/t0.5 ratio (28/40) is of the magnitude of 0.70. This suggests that a weekly (≈6.3 days) dosing interval in rats, (where the T/t0.5 ratio would be = 6.3/9 = 0.70) would be a fair and reasonable approximation to the monthly dosing interval in humans.

Taken all together, the results demonstrated that both CAB LA-MAP and CAB Na-MAP were successfully inserted in the skin, dissolved, and deposited comparable and substantial amounts of their drug cargo (≈20%), which were consistent with ex vivo results. The delivered doses by both MAPs were able to achieve drug plasma levels over 4× PA-IC90 over 28 days. Thus, both MAPs have potential to be used in ID delivery of CAB and could be used interchangeably. Although CAB FA-MAP exhibited similar properties in vivo, its delivery efficiency was very low (≈9%) in comparison, being ≈50% of that achieved by the other two MAPs, diminishing its potential for use.

2.6.2 CAB Pharmacokinetics After a Weekly Repeated Dose of CAB LA-MAP

To achieve the desired therapeutic effects, it is essential to use a robust drug delivery system that delivers a consistent dose upon each application and a dosing regimen that leads to drug accumulation to achieve and maintain steady-state drug concentrations in plasma (Css) within therapeutic levels. Therefore, in this study, in addition to safety and tolerability, we aimed i) to evaluate the ability of MAPs to repeatedly deliver a consistent dose post each application (MAP robustness) and the effect of MAP-delivered dose on CAB PK and ii) to assess whether repeated dosing that approximately mimics a monthly dosing regimen in humans would lead to drug accumulation and achieve steady-state drug plasma levels within the therapeutic concentration range, that is, 4× PA-IC90.

Since CAB LA is the established form of the drug and the previous in vivo study (where single doses were administered) demonstrated that CAB Na-MAP and CAB LA-MAP produced comparable PK profiles, the finalized CAB LA-MAP was selected as representative here.

Taking into consideration the results of the previous in vivo study in terms of the relative bioavailability of CAB from MAPs, the apparent t0.5 and the study aims, a dose of 2.5 mg/rat was selected as the dose to be administered to the rats once-weekly (to mimic once-monthly dosing in humans) on each of 4 weeks, in addition to other cohorts that received half of the dose by MAPs for the sake of comparison.

To this end, four cohorts were allocated for this study, two cohorts (cohorts 8 and 9) were used as controls, where each rat received a dose of 2.5 mg/rat of CAB LA (four times diluted by water) by IM or ID injection, respectively, and in the other two cohorts, each rat received the drug by MAPs either as 4× MAPs (cohort 10) or 2× MAPs (cohort 11). Plasma samples collected at predetermined time intervals over 42 days were analyzed by UPLC-MS-MS (Section S10, Supporting Information). CAB PK profiles are presented in Figure 5F and the key PK parameters, including the maximum drug concentration (Cmax−1) after the first dose, the time of maximum concentration (Tmax−1) after the first dose, the maximum drug concentration at the pseudo-steady-state (Cmax-ss), the time to reach the pseudo-steady-state maximum concentration (Tmax-ss), and the minimum drug concentration at the last sampling point (Ctrough), that is, (C42) at day 42, and the dose/body weight normalized PK parameters were determined (Section S11, Supporting Information) (Table 2) and used for comparison with the corresponding PK parameters achieved post-administering the drug by IM injection. Finally, drug accumulation (Cmax-ss/Cmax−1) and depreciation (Cmax-ss/C42) rates for each cohort were calculated and reported.

Table 2.
CAB pharmacokinetic parameters in Sprague Dawley rats following administering a repeated once-weekly dose of CAB LA by either IM or ID injection or MAP application. Data are reported as means ± SD, n ≥ 5
Experimental PK parameters Dose/body weight-normalized PK parametersa)
Cohort no. Drug form used/admin. route/device Dose[mg/kg] Tmax−1[days] Tmax-ss[days] Cmax−1[µg mL−1] Cmax-ss[µg mL−1] C42 days[µg mL−1] norm-Cmax−1[µg mL−1] norm-Cmax-ss[µg mL−1] norm-C42 days[µg mL−1]
8 CAB LA/IM

11.3

(±1.3)

7 15

54.5

(±6.8)

111.7

(±4.5)

33.8

(±8.5)

48.4

(±6.0)

100.3

(±4.0)

29.9

(±7.5)

9 CAB LA/ID

10.8

(±0.4)

7 22

28.8

(±4.4)

85.0

(±8.4)

48.0

(±5.8)

26.7

(±4.1)

78.2

(±7.7)

44.4

(±5.4)

10 CAB LA/4-MAP

51.9

(±1.8)

4 15

35.1

(±4.6)

60.3

(±10.7)

11.2

(±2.2)

27.1

(±3.5)

46.7

(±8.2)

8.6

(±1.7)

11 CAB LA/2-MAP

25.8

(±0.9)

4 15

17.5

(±5.5)

43.1

(±7.9)

9.6

(±3.2)

13.6

(±4.2)

33.4

(±6.2)

7.4

(±2.5)


  • a)

    The dose/body weight used for normalization was 10 mg/kg for cohorts 8 and 9; it was 40 and 20 mg/kg for cohorts 10 and 11, respectively, as described in the PK parameters calculation (Section S10, Supporting Information).

As can be seen from Figure 5F, in all cohorts the drug appeared in plasma within 1 h (the first sampling point) post-dosing and continued increasing in concentration upon administration of further doses. The plasma levels showed various patterns and that were dependent upon the administration route/device and the administered dose.

In those rats that received the drug by IM injection, CAB PK profiles showed a high plasma exposure, even higher than that in cohort 1 (where rats received 10 mg/rat doses), which is consistent with complete drug delivery and the effect of diluting CAB LA. The drug appeared in plasma within 1 h (the first sampling point) post-dosing and increased in concentration gradually to reach Cmax−1 at Tmax−1 (7 days). Administering further drug doses resulted in drug accumulation and continuous increase in drug plasma concentrations until day 15 (Tmax-ss = 15 days) (1-day post 3rd dose), where the drug reached its Cmax-ss and remained around this concentration for almost two weeks until day 28, Subsequently, drug concentration declined gradually to reach its (C42) at day 42. The drug concentration accumulation rate (Cmax-ss/Cmax−1) was ≈2.1. Drug concentration depreciation rate (Cmax-ss/C42) was 3.4.

In those rats that received the drug by ID injection (cohort 9), as expected, CAB exhibited a parallel PK profile. However, as in the single-dose study, Tmax-ss was longer (22 days, 1-day post the 4th dose). Also, Cmax−1, Cmax-ss, and C42 were significantly (p < 0.05) lower than those achieved by IM injection (Table 2). The drug concentration accumulation rate and depreciation rate were of the magnitude of ≈2.9 and 1.8, respectively, indicating that skin can retain the drug to a greater extent than muscle tissues. This is consistent with a decreased absorption rate in the skin due to the inherited differences in the anatomy and physiology between the skin and the muscle tissues, as discussed in the previous section.

Concerning CAB PK profiles, in rats that received 4× CAB LA-MAP (cohort 10), CAB again appeared in plasma within 1 h post-dosing and increased in concentration gradually to reach its Cmax after the first dose (Cmax−1) at day 4 (Tmax−1). Administering further drug doses, similarly to IM injection, resulted in drug accumulation and continuous increase in drug concentrations until day 15 (Tss) (1-day post 3rd dose), where the drug reached its Cmax-ss and remained around this concentration for almost two weeks until day 28, implying that the drug was accumulating in the skin, leading to drug concentrations fluctuating around Cmax-ss and then declining gradually to reach C42 (≈11.2 µg mL−1) at day 42. The drug concentration accumulation rate and depreciation rates were of the magnitude of ≈1.7 and ≈5.4, respectively, which are more closely related to those observed post-IM injection, rather than post-ID injection. This was again consistent with a relatively faster absorption rate (than from ID depots), due to the relatively large surface area provided by hundreds of micro-depots deposited in the skin by MAPs.

It is worth mentioning that the produced normalized Cmax-1, Cmax-ss, and C42 were 56.1%, 45.3%, and 29.4%, respectively, of the corresponding PK parameters observed after IM injection. However, if we take into consideration the dilution factor (four times dilution resulted in increased Cmax, (Section S12, Supporting Information) effect on those parameters produced by IM injection, Cmax-1 and Css produced by applying 4×CAB LA-MAP would be expected to be higher or equal to those produced if undiluted equivalent CAB LA doss were administered by IM injection.

In cohort 11 (rats that received 2× CAB LA-MAP containing 5.86 mg CAB LA, half of the dose received by rats in cohort 10), the plasma CAB concentrations were almost halved. For example, norm-Cmax−1 after the first dose was ≈13.6 µg mL−1, which is ≈50.3% of that observed after applying 4× CAB LA-MAP (≈27.1 µg mL−1) (Table 2), indicating that the MAPs were robust and can repeatedly deliver a consistent dose, which is proportional to the number of MAPs applied. The Cmax-ss (≈33.4 µg mL−1) was ≈72% of that observed after applying 4× CAB LA-MAP (≈33.4 µg mL−1), which is consistent with the reduced clearance due to the reduced dose. Also, drug plasma levels gradually decreased to reach C42 (≈7.4 µg mL−1) at day 42, which equates to ≈86.1% that observed after applying 4× CAB LA-MAP. This is still 11.1-fold above 4× PA-IC90. The drug concentration accumulation rate and depreciation rates were of the magnitude of ≈2.5 and ≈4.5, respectively. These are within the same range as the previous cohort, where 4× MAPs were applied, indicating that administering two different doses that varied by a factor of 2 did not significantly affect CAB PK in rats.

This study confirms that MAP administration of long-acting CAB is robust and was able to deliver a consistent dose upon application and achieve pseudo-steady-state concentrations after the 3rd dose, similar to that achieved with IM injection. CAB concentration patterns at steady-state were similar to those observed in humans following 800 mg loading dose by IM injection with a maintenance dose of 200 mg monthly by either IM or subcutaneous injection.[13, 70]

2.6.3 CAB-MAP Safety and Tolerability

Safety and tolerability are of paramount importance for any drug delivery system. We were testing our MAPs for the first time in vivo, and we were concerned about any potential side effects that may be induced. Therefore, MAP application sites were inspected for any signs of toxicity. Rat weights and behavior in all treatment groups, including controls, were monitored over the study periods and compared with a negative control cohort (where rats did not receive any drug). All treatments were well tolerated with no deaths or serious adverse effects observed. Importantly, rats that received the drug by MAPs did not show any sign of apparent irritation, infection, or any other skin complications post-application, apart from the expected mild erythema, which always subsided within a few hours after MAP removal. Additionally, no significant differences in weight gain were observed between the control and treatment groups (Section S4, Supporting Information), indicating that MAPs were safe and well-tolerated.

Source: Online Library, Wiley

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