Amikacin Liposome Inhalation Suspension (ALIS) Penetrates Non-tuberculous Mycobacterial Biofilms and Enhances Amikacin Uptake Into Macrophages.

Non-tuberculous mycobacteria (NTM) cause pulmonary infections in patients with structural lung damage, impaired immunity, or other risk factors. Delivering antibiotics to the sites of these infections is a major hurdle of therapy because pulmonary NTM infections can persist in biofilms or as intracellular infections within macrophages. Inhaled treatments can improve antibiotic delivery into the lungs, but efficient nebulization delivery, distribution throughout the lungs, and penetration into biofilms and macrophages are considerable challenges for this approach. Therefore, we developed amikacin liposome inhalation suspension (ALIS) to overcome these challenges. Nebulization of ALIS has been shown to provide particles within the respirable size range that distribute to both central and peripheral lung compartments in humans. The in vitro and in vivo efficacy of ALIS against NTM has been demonstrated previously. The key mechanistic questions are whether ALIS penetrates NTM biofilms and enhances amikacin uptake into macrophages. We found that ALIS effectively penetrated throughout NTM biofilms and concentration-dependently reduced the number of viable mycobacteria. Additionally, we found that ALIS improved amikacin uptake by ∼4-fold into cultured macrophages compared with free amikacin. In rats, inhaled ALIS increased amikacin concentrations in pulmonary macrophages by 5- to 8-fold at 2, 6, and 24 h post-dose and retained more amikacin at 24 h in airways and lung tissue relative to inhaled free amikacin. Compared to intravenous free amikacin, a standard-of-care therapy for refractory and severe NTM lung disease, ALIS increased the mean area under the concentration-time curve in lung tissue, airways, and macrophages by 42-, 69-, and 274-fold. These data demonstrate that ALIS effectively penetrates NTM biofilms, enhances amikacin uptake into macrophages, both in vitro and in vivo, and retains amikacin within airways and lung tissue. An ongoing Phase III trial, adding ALIS to guideline based therapy, met its primary endpoint of culture conversion by month 6. ALIS represents a promising new treatment approach for patients with refractory NTM lung disease.

Simultaneous Physiologically Based Pharmacokinetic (PBPK) Modeling of Parent and Active Metabolites to Investigate Complex CYP3A4 Drug-Drug Interaction Potential: A Case Example of Midostaurin.

Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by CYP3A4 to form two major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM. The model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole (a 5.8-fold predicted versus 6.1-fold observed increase) and rifampicin (90% predicted versus 94% observed reduction) as well as changes in midazolam exposure (1.0 predicted versus 1.2 observed ratio) after daily dosing of midostaurin for 4 days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors or inducers and the DDI potential with midazolam under steady-state conditions. The simulated midazolam area under the curve ratio of 0.54 and an accompanying observed 1.9-fold increase in the CYP3A4 activity of biomarker 4ß-hydroxycholesterol indicated a weak-to-moderate CYP3A4 induction by midostaurin and its metabolites at steady state in patients with advSM. In conclusion, a simultaneous parent-and-active-metabolite modeling approach allowed predictions under steady-state conditions that were not possible to achieve in healthy subjects. Furthermore, endogenous biomarker data enabled evaluation of the net effect of midostaurin and its metabolites on CYP3A4 activity at steady state and increased confidence in DDI predictions.

Evaluation of Clinical Drug Interaction Potential of Clofazimine Using Static and Dynamic Modeling Approaches.

The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (P450) inhibitor in vitro, a P450-mediated drug interaction may be likely when clofazimine is coadministered with substrates of these enzymes. The P450-mediated drug interaction potential of clofazimine was evaluated using both static [estimation of the R1 and area under the plasma concentration-time curve ratio (AUCR) values] and dynamic [physiologically based pharmacokinetics (PBPK)] modeling approaches. For static and dynamic predictions, midazolam, repaglinide, and desipramine were used as probe substrates for CYP3A4/5, CYP2C8, and CYP2D6, respectively. The AUCR static model estimations for clofazimine with the substrates midazolam, repaglinide, and desipramine were 5.59, 1.34, and 1.69, respectively. The fold increases in the area under the curve (AUC) predicted for midazolam, repaglinide, and desipramine with clofazimine (based on PBPK modeling) were 2.69, 1.60, and 1.47, respectively. Clofazimine was predicted to be a moderate-to-strong CYP3A4/5 inhibitor and weak CYP2C8 and CYP2D6 inhibitor based on the calculated AUCR by static and PBPK modeling. Additionally, for selected antiretroviral, antitubercular, antihypertensive, antidiabetic, antileprotics, and antihyperlipidemic CYP3A4/5 substrate drugs, approximately 2- to 6-fold increases in the AUC were predicted with static modeling when coadministered with 100 mg of clofazimine. Therefore, the possibility of an increase in the AUC of CYP3A4/5 substrates when coadministered with clofazimine cannot be ignored.

Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults.

BACKGROUND AND OBJECTIVES: Osilodrostat (LCI699) is an adrenal steroidogenesis inhibitor currently in late-phase clinical development as a potential treatment for Cushing's disease. This study evaluated the inhibitory effect of osilodrostat on the pharmacokinetics of probe substrates of the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2D6, and CYP3A4. METHODS: Healthy adult volunteers received single-dose cocktail probe substrates [caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg)] followed by a 6-day washout. Subjects then received a single dose of osilodrostat 50 mg followed by a single dose of cocktail probe substrates. RESULTS: Nineteen of twenty subjects (ten were male) completed the study. Mean age, body weight, and body mass index were 41.8 years, 73.0 kg, and 24.4 kg/m2. Geometric mean ratio of the area under the concentration-time curve from time zero to the last measureable concentration and 90% confidence intervals of probe substrate exposure with osilodrostat were: caffeine (CYP1A2 probe substrate), 2.33 (2.10-2.59); omeprazole (CYP2C19), 1.91 (1.74-2.11); dextromethorphan (CYP2D6), 1.48 (1.34-1.63); and midazolam (CYP3A4/5), 1.50 (1.41-1.60). Corresponding values for geometric mean ratio of maximum plasma concentration (90% confidence interval) for the change in substrate exposure were 1.07 (0.988-1.15), 1.61 (1.40-1.84), 1.35 (1.21-1.50), and 1.47 (1.32-1.62). CONCLUSIONS: Osilodrostat is a moderate inhibitor of CYP1A2 and CYP2C19 and a weak inhibitor of CYP2D6 and the most clinically important CYP enzyme, CYP3A4. Osilodrostat is unlikely to significantly increase the exposures of other medications cleared by CYP3A4. These findings are clinically relevant given that Cushing's disease is a chronic condition often requiring multiple medications and that most other therapies have significant drug interaction potential.