27 A New Method for Initiating Treatment with the Long-acting Antipsychotic Aripiprazole Lauroxil

AbstractSTUDY OBJECTIVESlow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.METHODSA blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.RESULTSThe PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.CONCLUSIONSThe 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.Funding Acknowledgements: This study was funded by Alkermes Inc.

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Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00163-19 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 3

Author(s):

Laura L. Kovanda ◽

Sean M. Sullivan ◽

Larry R. Smith ◽

Amit V. Desai ◽

Pete L. Bonate ◽

...

Keyword(s):

Antifungal Agent ◽

Healthy Subjects ◽

Phase 1 ◽

Plasma Concentrations ◽

Population Pharmacokinetic ◽

Binding Model ◽

Saturable Binding ◽

Drug Concentrations ◽

Over Time

ABSTRACT VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.

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Association analysis of polymorphisms in genes related to sunitinib pharmacokinetics.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4580 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4580-4580

Author(s):

Meta Diekstra ◽

Heinz Josef Klümpen ◽

Martijn P. J. K. Lolkema ◽

Huixin Yu ◽

Jacqueline S.L. Kloth ◽

...

Keyword(s):

Drug Exposure ◽

Plasma Concentrations ◽

Significant Snps ◽

Population Pharmacokinetic ◽

Nucleotide Polymorphisms ◽

Replication Studies ◽

Significance Threshold ◽

Potential Association ◽

Individual Snps ◽

Genes Encoding

4580 Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p<0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p<0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p<0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p<0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.

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Phase I dose-escalation study of pasireotide LAR in patients with advanced neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15126 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15126-e15126 ◽

Cited By ~ 1

Author(s):

Alexandria T. Phan ◽

Edward M. Wolin ◽

Jennifer A. Chan ◽

Jerry M. Huang ◽

Michelle Hudson ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Somatostatin Receptor ◽

Plasma Concentrations ◽

Median Number ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Best Response ◽

Long Acting

e15126 Background: Somastatin analogs (SSA), including octreotide and lanreotide, bind predominantly to somatostatin receptor (SSTR) 2 and form the foundation of treatment for symptomatic neuroendocrine tumors (NET). Pasireotide, a novel SSA with a broad binding affinity (SSTR 1-3 and 5), is being explored for treatment of NET. A phase 1 dose-escalation study (NCT01364415) of pasireotide long-acting release (LAR; starting dose of 80 mg) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and to characterize safety, tolerability, pharmacokinetics, and efficacy in pts with advanced NET. Methods: Pts with advanced, well- or moderately differentiated NET received pasireotide LAR beginning at a dose of 80 mg q28d. Successive cohorts will receive doses (up to 220 mg) guided by a Bayesian logistic regression model until MTD/RP2D is reached. Results: To date, 15 pts have been treated at 80 mg (n=6) and 120 mg (n=9). Median age is 59 (44-76) years. Primary tumor sites include small intestine (40%), pancreas (20%), and lung (13.3%). All pts received prior antineoplastic therapy; 93% received prior SSA. Median number of cycles of pasireotide was 6.68 (2-14) (1 cycle=28 days). 10 (67%) pts remain on treatment: 3 on 80 mg and 7 on 120 mg. 5 (33%) have discontinued (disease progression, 2 pts; withdrew consent, 2 pts; adverse event [AE], 1 pt). Median plasma concentrations of pasireotide increased with dose. No dose-limiting toxicities have been reported. Most frequent AEs were similar in both dose groups and included hyperglycemia (87%), diarrhea (53%), abdominal pain (47%), nausea (40%), anemia (33%), and fatigue (33%). Most AEs were mild/moderate. 2 pts (1 in each group) had grade 3 hyperglycemia. 4 (27%) and 2 (13%) pts had HbA1C increase from <6.5% at baseline to 6.5-<8% and ≥8%, respectively. 13 (87%) pts had radiographically stable disease as best response. More pts at 120 mg (50%) vs 80 mg (33%) achieved ≥50% reduction in chromogranin A. Conclusions: Pasireotide LAR up to 120 mg appears to be well tolerated in patients with advanced NET. The study is ongoing. Pasireotide represents a promising therapy for pts with NET. Clinical trial information: NCT01364415.

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Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure

10.21203/rs.2.13120/v2 ◽

2019 ◽

Author(s):

Christian Siebel ◽

Gudrun Würthwein ◽

Claudia Lanvers-Kaminsky ◽

Nicolas André ◽

Frank Berthold ◽

...

Keyword(s):

Young Children ◽

Drug Exposure ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Population Pharmacokinetic ◽

Delphi Consensus ◽

Treatment Regimens ◽

Consensus Procedure ◽

Dosing Strategies ◽

Pharmacokinetic Simulations

Abstract Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.

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Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure

10.21203/rs.2.13120/v3 ◽

2020 ◽

Author(s):

Christian Siebel ◽

Gudrun Würthwein ◽

Claudia Lanvers-Kaminsky ◽

Nicolas André ◽

Frank Berthold ◽

...

Keyword(s):

Young Children ◽

Drug Exposure ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Population Pharmacokinetic ◽

Delphi Consensus ◽

Treatment Regimens ◽

Consensus Procedure ◽

Dosing Strategies ◽

Pharmacokinetic Simulations

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P515 Comparability of upadacitinib pharmacokinetics in Japanese and non-Japanese subjects with ulcerative colitis with the extended-release formulation

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.643 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S446-S446

Author(s):

S Stodtmann ◽

A Friedel ◽

W Zhou ◽

M E MOHAMED

Keyword(s):

Ulcerative Colitis ◽

Extended Release ◽

Inflammatory Diseases ◽

Phase 1 ◽

Dose Range ◽

Plasma Concentrations ◽

Population Pharmacokinetic ◽

Release Formulation ◽

Extended Release Formulation ◽

Japanese Subjects

Abstract Background Upadacitinib (UPA), an oral selective JAK1 inhibitor, is being developed for treatment of patients with moderately-to-severely active ulcerative colitis (UC) in addition to several other inflammatory diseases. UPA has shown favourable efficacy and acceptable safety in UC in an 8-week double-blind placebo-controlled dose-ranging Phase 2b induction study in subjects with moderately-to-severely active UC (U-ACHIEVE trial). Methods Sparse blood samples were collected from subjects with UC who were enrolled in the U-ACHIEVE trial, which included Japanese and non-Japanese subjects. UPA plasma concentration vs. time after dose were summarised from the U-ACHIEVE trial. Additionally, data from U-ACHIEVE were pooled with data from UPA Phase 1 and other Phase 2 studies across different inflammatory diseases to characterise UPA population pharmacokinetics. The population pharmacokinetic model was used to estimate UPA plasma exposures from extended-release formulation (dose range 7.5 – 45mg QD) in 168 non-Japanese and 28 Japanese subjects with UC in U-ACHIEVE. Results UPA plasma exposures were approximately dose proportional over the evaluated dose range in Japanese subjects with UC. Observed dose-normalised plasma concentrations vs. time since the last dose (Figure 1) and dose-normalised model-estimated UPA exposures were comparable (within 25%) between Japanese and non-Japanese subjects with UC (Table 1). Conclusion UPA plasma exposures are similar between Japanese and non-Japanese subjects with UC. This is in agreement with prior assessments in healthy subjects and in subjects with RA which demonstrated comparable UPA exposures between Asian and Western subjects.

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Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.2118 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S572-S572

Author(s):

J. Llaudó ◽

L. Anta ◽

I. Ayani ◽

J. Martínez-González ◽

I. Gutierro ◽

...

Keyword(s):

Steady State ◽

Dopamine D2 Receptor ◽

Plasma Concentrations ◽

Phase Iii ◽

Population Pharmacokinetic ◽

Two Phase ◽

Phase Iii Trial ◽

Population Pharmacokinetic Modeling ◽

Population Pk ◽

Long Acting

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Safety and Population Pharmacokinetic Analysis of Intravenous Acetaminophen in Neonates, Infants, Children, and Adolescents With Pain or Fever

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-16.4.246 ◽

2011 ◽

Vol 16 (4) ◽

pp. 246-261 ◽

Cited By ~ 1

Author(s):

Athena F. Zuppa ◽

Gregory B. Hammer ◽

Jeffrey S. Barrett ◽

Brian F. Kenney ◽

Nastya Kassir ◽

...

Keyword(s):

Children And Adolescents ◽

Phase 1 ◽

Plasma Concentrations ◽

Age Groups ◽

Rectal Administration ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Intravenous Acetaminophen

OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

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No Dose Adjustment for Isavuconazole Based on Age or Sex

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02629-18 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 5

Author(s):

Amit V. Desai ◽

David Han ◽

Donna L. Kowalski ◽

Christopher Lademacher ◽

Helene Pearlman ◽

...

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Phase 1 ◽

Plasma Concentrations ◽

Population Pharmacokinetic ◽

Elderly Age ◽

Open Label ◽

Absorption Function ◽

Significant Toxicity ◽

Males And Females

ABSTRACT This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336 h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.)

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Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1265 ◽

2020 ◽

Cited By ~ 1

Author(s):

Andrew D McCallum ◽

Henry E Pertinez ◽

Laura J Else ◽

Sujan Dilly-Penchala ◽

Aaron P Chirambo ◽

...

Keyword(s):

Pulmonary Tuberculosis ◽

Drug Exposure ◽

Plasma Concentrations ◽

Clinical Treatment ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

High Dose ◽

Alveolar Cells ◽

First Line ◽

Drug Concentrations

Abstract Background Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis. Methods Malawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics. Results One-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2–18.0-fold) and 49.8-fold (95% CI, 34.2–65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell–plasma ratio, 15.0; 95% CI, 11.4–18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response. Conclusions We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.

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