Table 5.
The PBMC-to-plasma drug ratios for all three antiretrovirals, compared to oral dosing reference, after a single subcutaneous dose of a long-acting drug combination formulation (TLC-ART101). The enhanced PBMC-to-plasma ratio following one subcutaneous dose of TLC-ART101 compared to the same drugs given orally suggest cell targeting effects are mediated by the TLC-ART nano-drug combination particles.
| Species | Humans | Monkeys | ||||
|---|---|---|---|---|---|---|
| Reference | [147] | [147] | [186] | [61] | ||
| Route | PO | PO | PO | SC | ||
| Formulation | Kaletra® | Kaletra® | Viread® | TLC-ART101 | ||
| Drug | LPV | RTV | TFV | LPV | RTV | TFV |
| Dose (mg/kg) | 22.9a | 5.7a | 2.4b | 25.0 | 7.0 | 10.6 |
| Time | 16 hr | 16 hr | 24 hr | AUC(0–336hr)c | AUC(0–336hr)c | AUC(0–336hr)c |
|
PBMC Drug Level |
2.7 µg/mL | 0.23 µg/mL | 26 ng/mLd | 44 hr•µg/mL | 35 hr•µg/mL | 1.3 hr•mg/mL |
|
Plasma Drug Level |
10 µg/mL | 0.45 µg/mL | 40 ng/mL | 11 hr•µg/mL | 4.8 hr•µg/mL | 0.42 hr•mg/mL |
|
Ratio of PBMC/Plasma Drug Levels |
0.27 | 0.52 | 0.65 | 4.02 | 7.40 | 3.01 |
The median age of patients in the van Kampen et al. 2010 study was 10 years old. Since dose and median weight were not reported in this study, we used the recommended dose of 800 mg LPV/200 mg RTV administered once daily as Kaletra® for children weighing 35 kg (which is the median weight of children 10 years old) to calculate the mg/kg dose for LPV and RTV given in this study.
The oral dose for TFV in humans was calculated for 300 mg tenofovir disoproxil fumarate (TDF; 519.44 g/mol) and assuming 70 kg human weight as follows: (300 mg TDF/70 kg) x (287.21 g/mol TFV/519.44 g/mol TDF) = 2.4 mg/kg.
Because complete drug concentration-time course profiles over two weeks (0–336 hr) were characterized for LPV, RTV, and TFV in monkeys after TLC-ART101 dosing, AUC(0–336h) values were used to calculate the PBMC/Plasma Ratio for each drug.
Since only tenofovir diphosphate (TFV-DP) drug levels in PBMCs were reported in [186], the steady-state fraction of 61% of total intracellular TFV being TFV-DP was used to estimate the total intracellular TFV level reported in the table (26 ng/mL) [187–190]. For these calculations, the PBMC cell volume was assumed to be 0.2829 pL/cell [185].
AUC(0–336hr), area under the concentration-time curve between time 0 to 336 hours; PBMC, peripheral blood mononuclear cell; PO, oral; SC, subcutaneous; LPV, lopinavir; RTV, ritonavir; TFV, tenofovir.