Phase I Trial of Histone Deacetylase Inhibition by Valproic Acid Followed by the Topoisomerase II Inhibitor Epirubicin in Advanced Solid Tumors: A Clinical and Translational Study

2007 ◽  
Vol 25 (15) ◽  
pp. 1979-1985 ◽  
Author(s):  
Pamela Münster ◽  
Douglas Marchion ◽  
Elona Bicaku ◽  
Morgen Schmitt ◽  
Ji Hyun Lee ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Histone Deacetylase ◽  
Topoisomerase Ii ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase Inhibition

Purpose To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. Patients and Methods Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. Results Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. Conclusion The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.

Phase I trial of panobinostat (P) and imatinib (IM) in patients with treatment-refractory gastrointestinal stromal tumors (GIST).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10032-10032
Author(s):  
Sebastian Bauer ◽  
Ralf A. Hilger ◽  
Florian Grabellus ◽  
James Nagarajah ◽  
Mathias Hoiczyk ◽  
...  
Keyword(s):  
Phase I ◽  
Mononuclear Cells ◽  
Metabolic Response ◽  
Combined Treatment ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Peripheral Blood Mononuclear

10032^ Background: Panobinostat (LBH589; P) is a pan-deacetylase-inhibitor that has preclinical activity in combination with IM in GIST models in vitro and in vivo. Aim of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of escalating doses of P in combination with IM in patients with GIST who have failed IM and sunitinib treatment. Methods: This was a two-center phase I study using a 3+3 design with a prespecified expansion of the MTD cohort. IM was administered at a dose of 400mg qd. Following a 7 day run-in phase, escalating doses of P were added. The starting dose for P was 20 mg given as a three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Doses were increased by 10 mg if no dose limiting toxicities emerged. Blood samples were drawn for PK and biomarker assessments of IM, its main metabolite N-desmethyl-IM, and P using a validated RP-HPLC method. Acetylation of histone A3 was evaluated in peripheral blood mononuclear cells (PBMNC) as pharmacodynamic marker for P activity. Metabolic response using PET (EORTC-PET study criteria) was assessed on day 7 of IM run-in and after 3 weeks of combined treatment with IM and P. Results: In total 12 extensively pretreated (median 5 pretreatments) pts (4 f, 8 m; median age 56 y, 34-75 y) received study treatment at 2 dose levels (DL). 2 dose-limiting toxicities (grade 4 thrombocytopenia) occurred at DL 2 (30 mg). Most common AEs were thrombocytopenia, anemia, fatigue, nausea, emesis, diarrhea, creatinine elevation, abdominal cramping, and weight loss. DL 1 (20mg) was declared MTD, and 5 additional pts were enrolled at DL1. Analysis of P and IM PK revealed mean peak concentration of 14.8 +/- 9.5 ng/ml for P (20 mg). IM plasma concentrations with 400 mg once-daily administration were 2.8 ± 1.1 μg/mL at peak and 1.2 ± 0.4 μg/mL at trough. Histone A3 acetylation was demonstrated in PBMNC from pts treated at DL 1. 11 pts were evaluable for PET response: 1 had mPR, 7 had mSD and 3 had mPD. Longest treatment duration was 17 weeks (median: 6wks). Conclusions: P in combination with IM is moderately tolerated. Evidence of target inhibition at the MTD was associated with limited clinical activity in heavily pretreated pts with GIST.

Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma

2005 ◽  
Vol 23 (17) ◽  
pp. 3912-3922 ◽  
Author(s):  
Qin C. Ryan ◽  
Donna Headlee ◽  
Milin Acharya ◽  
Alex Sparreboom ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylase ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase Inhibition ◽  
Daily Schedule ◽  
Blood Mononuclear Cells

PurposeThe objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275.Patients and MethodsPatients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily × 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2and the dose was escalated in three- to six-patient cohorts based on toxicity assessments.ResultsWith the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for ≥ 3 months.ConclusionThe MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly × 4, repeated every 6 weeks is presently being evaluated.

Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13036-13036 ◽  
Author(s):  
E. A. Donovan ◽  
A. Sparreboom ◽  
W. Figg ◽  
J. Trepel ◽  
K. Maynard ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Interindividual Variability ◽  
Protein Acetylation ◽  
Hdac Inhibition ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Grade 3

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]

Phase I, pharmacokinetic (PK), pharmacodynamic study of paricalcitol [19-nor-1 alpha, 25-(OH)2 D2] in combination with gemcitabine [2’,2’ difluorodeoxycytidine] in patients with advanced malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12010-12010
Author(s):  
D. Trump ◽  
M. Javle ◽  
J. Muindi ◽  
L. Pendyala ◽  
W. Yu ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Cytidine Deaminase ◽  
Maximum Tolerated Dose ◽  
Chemotherapeutic Agents ◽  
Fixed Dose ◽  
Unknown Primary ◽  
Peripheral Blood Mononuclear

12010 Background: Calcitriol+ gemcitabine (gem) combination results in synergistic anti-tumor effect in preclinical models. Cytidine deaminase (CDD) inactivates gem into 2’,2’-difluorodeoxyuridine (dFdU) and its overexpression may lead to gem resistance. Calcitriol decreases CDD activity in peripheral blood mononuclear cells (PBM). Paricalcitol is cytotoxic in vitro and synergistic with several chemotherapeutic agents, including gem. We are conducting a phase I study of paricalcitol + fixed-dose gem. Objectives: The primary aim is to determine maximum tolerated dose (MTD) of the combination in patients (pts) with advanced cancer. Secondary aims are to evaluate toxicity, the effect of paricalcitol on gem PK, CDD activity in PBM and clinical outcome. Methods: Each cycle is 4 weeks: Gem 800 mg/m2 (over 80 min) weekly × 3, starting day 1; paricalcitol weekly, 24 h prior to gem, starting day 7. Standard 3+3 dose-escalation schema is used. Planned paricalcitol doses are 0.24, 0.72, 1.20, 1.8, 2.4 μg/kg, and 25% increments till MTD. Gem PK and CDD activity (PBM) are studied on days 1 and 8. Paricalcitol PK studies are obtained on day 7. Results: Fourteen pts with the following cancers: pancreatic (n=3), colon (n=3), lung (n=5), esophageal (n=1), bladder (n=1) and unknown primary (n=1) have been enrolled. No dose limiting toxicities have occurred. Median of 2 cycles were delivered (range 1–9). Grade 3 toxicities: anemia (n=3 pts), neutropenia (n=5), thrombocytopenia (n=3), thrombosis (n=2), anorexia (n=1), hypophosphatemia (n=1), dehydration (n=1), syncope (n=1), pneumonia (n=1) and chills (n=1). Grade 4 toxicities: anemia (n=1) and neutropenia (n=1). Hypercalcemia (> grade 1) did not occur. Stable disease occurred in 2 and progressive disease in 3. Conclusions: MTD was not reached at 1.8 μg/kg of paricalcitol with gem 800 mg/m2/week. Dose escalation is ongoing. PK data will be presented at meeting. Supported by NIH grants CA67267 and CA85142. [Table: see text]

A first-in-man phase I study of R306465, a histone deacetylase (HDAC) inhibitor exploring pharmacokinetics (PK) and pharmacodynamics (PD) utilizing an electrochemiluminescent immunoassay in patients (p) with advanced tumours

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3578-3578 ◽  
Author(s):  
P. C. Fong ◽  
S. Settatree ◽  
R. Sinha ◽  
A. Hardcastle ◽  
P. W. Hellemans ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Hdac Inhibitors ◽  
Fold Increase ◽  
Maximum Tolerated Dose ◽  
Transcriptional Level ◽  
Peripheral Blood Mononuclear ◽  
Fed State ◽  
Class 1 ◽  
Ecog Ps

3578 Background: R306565 is an aromatic hydroxamic acid with predominant inhibitory effects on Class 1 HDAC enzymes (with IC50 ∼10 nM). HDAC inhibitors (HDACi) affect gene expression at the transcriptional level, leading to cell cycle arrest and induction of apoptosis. Methods: P with solid tumours or lymphoma were given R306465 orally daily for 3 weeks (w) out of 4 in an escalating schedule. Objectives include safety, tolerability, PK (including food effect exploration), PD evaluation and circulating tumour cell (CTC) quantitation. Results: Four dose levels (100, 200, 300 and 400 mg) have been evaluated involving 15 p (7 male), age range 29–72 (median 59 y) and ECOG PS 0–2. A total of 37 cycles have been administered. Most common adverse events (AE) were Grade (G) 1–3 fatigue (87%), G1–2 nausea (66%), G1–2 vomiting (33%), G1–2 diarrhoea (40%), and G1–2 anorexia (40%). Dose limiting toxicity of G3 fatigue was seen in 1/6 p in the 400mg cohort. PK parameters were approximately dose proportional. Plasma concentrations increased in the fed state. PD effect of histone H3 acetylation (AcH3) in peripheral blood mononuclear cells (PBMC) was determined quantitatively with a novel validated electrochemiluminescent immunoassay developed in-house (applying Mesoscale Discovery technology). Although some interpatient variability exists, increased AcH3 was observed in 2/6 p in the 400 mg cohort, while the percentage rise in AcH3 was minimal for cohorts 1–3. Peak AcH3 achieved in 2 p dosed at 400 mg was approximately 5–10 fold increase over baseline. Using CellSearch technology for quantitation of CTCs, 8/14 p had detectable CTCs at baseline; the CTC trend will be presented. 4 p had stable disease (SD) for = 4 months. Conclusions: R306465 could be safely administered on a daily dosing schedule for 3 of 4 w up to 400 mg. Common toxicities seen were gastrointestinal and fatigue. Maximum tolerated dose has not been reached. PK suggests dose proportionality. Promising PD data showing increased acetylation in PBMC at 400 mg, further supports the utilization of the immunoassay platform in HDACi clinical trials. No significant financial relationships to disclose.

Phase I clinical, pharmacokinetic, and pharmacodynamic study of CG200745, a histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13560-e13560
Author(s):  
Kyu-Pyo Kim ◽  
Yong Sang Hong ◽  
Jin-Hee Ahn ◽  
Jae-Lyun Lee ◽  
Kyun-Seop Bae ◽  
...  
Keyword(s):  
Single Dose ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Elimination Half ◽  
Solid Malignancies ◽  
Acetylated Histone H4

e13560 Background: The aim of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single dose of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Methods: Two to six patients received Intravenous CG200745 every 3 weeks according to the single dose-escalating 2+4 method. Acetylated histone H4 (Acetyl-H4) was measured in peripheral blood mononuclear cells (PBMCs). Results: Ten patients were treated at one of five doses (1.8-24.0 mg/m2) and received 3 (1-7) cycles of CG200745 (median, range). No dose-limiting toxic effects or QTc prolongations were noted. Dose proportionality was observed for both Cmax and AUC. The elimination half-life and mean residual time was 5.43±0.37(mean±SD) and 4.15±0.50 hrs. An increase in Acetyl-H4 was observed at hour 1 and correlated with dose and Cmax. Acetyl-H4 persisted for 8 hrs in 3 pts and 24 hrs in another 3 pts. Stable disease was seen in 2 pts with colorectal cancer at levels 7.2 and 24 mg/m2. Conclusions: CG200745 can be safely administered at the effective dose levels that inhibit HDAC in PBMCs. As MTD was not reached, this agent is under further investigation for multiple ascending doses.

A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 219-219
Author(s):  
Michael Thomas Schweizer ◽  
Aditya Bardia ◽  
Amanda L. Blackford ◽  
Jianqing Lin ◽  
Andrew J. Armstrong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Local Therapy ◽  
Median Number ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Psa Progression

219 Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines. Methods: To determine if D leads to demethylation changes [i.e. decreased global 5meC DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating “response” (i.e. >10% decrease in global 5meC content) in <3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed >50% rise over baseline and >2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability. Results: Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had >10% decrease in global 5meC content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms. Conclusions: A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population. Clinical trial information: NCT01118741.

scholarly journals Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

2015 ◽  
Vol 59 (4) ◽  
pp. 2179-2188 ◽  
Author(s):  
Liviawati S. Wu ◽  
Joseph E. Rower ◽  
James R. Burton ◽  
Peter L. Anderson ◽  
Kyle P. Hammond ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Mononuclear Cells ◽  
Formation Rate ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Peripheral Blood Mononuclear ◽  
First Order

ABSTRACTRibavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effectsin vitro, but the kinetics of these phosphorylated moieties have not been fully elucidatedin vivo. We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.)

scholarly journals Relationship between plasma and intracellular concentrations of bedaquiline and its M2 metabolite in South African patients with rifampin-resistant TB

2021 ◽  
Author(s):  
Precious Ngwalero ◽  
James C.M. Brust ◽  
Stijn W. van Beek ◽  
Sean Wasserman ◽  
Gary Maartens ◽  
...  
Keyword(s):  
High Performance ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Primary Metabolite ◽  
Peripheral Blood Mononuclear ◽  
Plasma Ratio ◽  
Intracellular Concentrations

Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2 and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used non-compartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 – 2540 ng/mL in plasma and 16.2 – 5478 ng/mL in PBMCs and concentrations of M2 over the six-month treatment period ranged from 34.3 – 496 ng/mL in plasma and 109.2 – 16764 ng/mL in PBMCs. Plasma concentrations of bedaquiline were higher than M2, but intracellular concentrations of M2 were considerably higher than bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratio 1 and 2 months after start of treatment was 0.61 (95%CI: 0.42-0.92) and 1.10 (95%CI: 0.74-1.63) for bedaquiline and 12.4 (95%CI: 8.8-17.8) and 22.2 (95%CI: 15.6-32.3) for M2. The intracellular-plasma ratio for both bedaquiline and M2 was decreased by 54% (95%CI: 24-72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.

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