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Article ; Online: Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development.

Abd-Rahman, Azrin N / Zaloumis, Sophie / McCarthy, James S / Simpson, Julie A / Commons, Robert J

2021 Volume 66, Issue 2, Page(s) e0165921

Abstract: The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II ... ...

Abstract	The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II studies between 1 January 2016 and 28 April 2021. PubMed, Web of Science, Embase, clinical trial registries, and reference lists were searched for relevant studies. Information regarding antimalarial compound details, clinical trial characteristics, study population, and drug pharmacokinetics and pharmacodynamics (PK-PD) were extracted. A total of 50 studies were included, of which 24 had published their results and 26 were unpublished. New antimalarial compounds were evaluated as monotherapy (28 studies, 14 drug candidates) and combination therapy (9 studies, 10 candidates). Fourteen active compounds were identified in the current antimalarial drug development pipeline together with 11 compounds that are inactive, 6 due to insufficient efficacy. PK-PD data were available from 24 studies published as open-access articles. Four unpublished studies have made their results publicly available on clinical trial registries. The terminal elimination half-life of new antimalarial compounds ranged from 14.7 to 483 h. The log
MeSH term(s)	Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Drug Development ; Drug Resistance ; Humans ; Malaria, Falciparum/drug therapy ; Plasmodium falciparum
Chemical Substances	Antimalarials
Language	English
Publishing date	2021-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01659-21
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Article ; Online: Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum.

McCarthy, James S / Abd-Rahman, Azrin N / Collins, Katharine A / Marquart, Louise / Griffin, Paul / Kümmel, Anne / Fuchs, Aline / Winnips, Cornelis / Mishra, Vishal / Csermak-Renner, Katalin / Jain, J Prakash / Gandhi, Preetam

Antimicrobial agents and chemotherapy

2021 Volume 65, Issue 2

Abstract: The spiroindolone cipargamin, a new antimalarial compound that ... ...

Abstract	The spiroindolone cipargamin, a new antimalarial compound that inhibits
MeSH term(s)	Animals ; Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Healthy Volunteers ; Humans ; Indoles ; Malaria, Falciparum/drug therapy ; Plasmodium falciparum ; Spiro Compounds
Chemical Substances	Antimalarials ; Indoles ; NITD 609 ; Spiro Compounds
Language	English
Publishing date	2021-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01423-20
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Article ; Online: Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

Barber, Bridget E / Abd-Rahman, Azrin N / Webster, Rebecca / Potter, Adam J / Llewellyn, Stacey / Marquart, Louise / Sahai, Nischal / Leelasena, Indika / Birrell, Geoffrey W / Edstein, Michael D / Shanks, G Dennis / Wesche, David / Moehrle, Joerg J / McCarthy, James S

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2023 Volume 76, Issue 11, Page(s) 1919–1927

Abstract: ... Results: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n ... 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours ...

Abstract	Background: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals. Methods: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. Conclusions: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).
MeSH term(s)	Adult ; Humans ; Antimalarials/adverse effects ; Plasmodium falciparum ; Healthy Volunteers ; Parasitemia/drug therapy ; Artemether/pharmacology ; Artemether/therapeutic use ; Artemether, Lumefantrine Drug Combination/therapeutic use ; Australia ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/parasitology
Chemical Substances	Antimalarials ; tafenoquine (262P8GS9L9) ; Artemether (C7D6T3H22J) ; Artemether, Lumefantrine Drug Combination
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciad075
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Article ; Online: Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study.

Abd-Rahman, Azrin N / Marquart, Louise / Gobeau, Nathalie / Kümmel, Anne / Simpson, Julie A / Chalon, Stephan / Möhrle, Jörg J / McCarthy, James S

Clinical pharmacology and therapeutics

2020 Volume 108, Issue 5, Page(s) 1055–1066

Abstract: Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD ... ...

Abstract	Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood-stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour
MeSH term(s)	Administration, Oral ; Adult ; Antimalarials/administration & dosage ; Antimalarials/blood ; Antimalarials/pharmacokinetics ; Biotransformation ; Chloroquine/administration & dosage ; Chloroquine/analogs & derivatives ; Chloroquine/blood ; Chloroquine/pharmacokinetics ; Drug Dosage Calculations ; Drug Resistance ; Female ; Humans ; Malaria, Vivax/blood ; Malaria, Vivax/diagnosis ; Malaria, Vivax/drug therapy ; Malaria, Vivax/parasitology ; Male ; Models, Biological ; Parasite Load ; Plasmodium vivax/drug effects ; Plasmodium vivax/growth & development ; Treatment Outcome ; Young Adult
Chemical Substances	Antimalarials ; Chloroquine (886U3H6UFF) ; desethylchloroquine (ZC9Z9XX2PD)
Keywords	covid19
Language	English
Publishing date	2020-07-02
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.1893
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Article ; Online: Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection.

Collins, Katharine A / Abd-Rahman, Azrin N / Marquart, Louise / Ballard, Emma / Gobeau, Nathalie / Griffin, Paul / Chalon, Stephan / Möhrle, Jörg J / McCarthy, James S

The Journal of infectious diseases

2020 Volume 225, Issue 6, Page(s) 1062–1069

Abstract: Background: Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug ... ...

Abstract	Background: Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate. Methods: Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility. Results: Initial parasite clearance occurred in all participants after artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11-14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4-8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. Conclusions: The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria. Clinical trials registration: NCT02573857.
MeSH term(s)	Adamantane/analogs & derivatives ; Animals ; Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Culicidae ; Folic Acid Antagonists/pharmacology ; Humans ; Malaria, Falciparum/parasitology ; Malaria, Vivax/drug therapy ; Parasites ; Peroxides ; Plasmodium falciparum ; Plasmodium vivax
Chemical Substances	Antimalarials ; Folic Acid Antagonists ; Peroxides ; Adamantane (PJY633525U) ; artefenomel (RIK029813G)
Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiaa287
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Article: Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study

Abd-Rahman, Azrin N / Marquart, Louise / Gobeau, Nathalie / Kümmel, Anne / Simpson, Julie A / Chalon, Stephan / Möhrle, Jörg J / McCarthy, James S

Clin Pharmacol Ther

Abstract	Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood-stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour-1 (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #277084
Database	COVID19

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Article ; Online: Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.

The Lancet. Infectious diseases

2022 Volume 22, Issue 6, Page(s) 879–890

Abstract: Background: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium ... ...

Abstract	Background: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. Methods: A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). Findings: 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5-16·0] after dosing in the fed state vs 6·0 h [4·5-9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0·013 [90% CI -0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2-6·9] for 200 mg, 6·8 h [95% CI 6·5-7·1] for 300 mg, and 7·1 h [95% CI 6·6-7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 10 Interpretation: The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. Funding: Cadila Healthcare and Medicines for Malaria Venture.
MeSH term(s)	Adult ; Antimalarials/adverse effects ; Australia ; Double-Blind Method ; Humans ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/parasitology ; Parasitemia ; Pilot Projects ; Volunteers
Chemical Substances	Antimalarials
Language	English
Publishing date	2022-03-02
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(21)00679-4
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Article ; Online: Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis.

Abd Rahman, Azrin N / Tett, Susan E / Abdul Gafor, Halim A / McWhinney, Brett C / Staatz, Christine E

European journal of drug metabolism and pharmacokinetics

2017 Volume 42, Issue 6, Page(s) 993–1004

Abstract: Background and objective: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim ...

Abstract	Background and objective: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. Methods: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. Results: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM Conclusion: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.
MeSH term(s)	Adult ; Computer Simulation ; Cyclosporine/pharmacology ; Drug Dosage Calculations ; Drug Interactions ; Female ; Glucuronides/blood ; Glucuronides/pharmacokinetics ; Humans ; Immunosuppressive Agents/blood ; Immunosuppressive Agents/pharmacokinetics ; Immunosuppressive Agents/therapeutic use ; Lupus Nephritis/blood ; Lupus Nephritis/drug therapy ; Male ; Middle Aged ; Models, Biological ; Mycophenolic Acid/analogs & derivatives ; Mycophenolic Acid/blood ; Mycophenolic Acid/pharmacokinetics ; Mycophenolic Acid/therapeutic use ; Young Adult
Chemical Substances	Glucuronides ; Immunosuppressive Agents ; mycophenolic acid glucuronide (54TS5J9T0K) ; Cyclosporine (83HN0GTJ6D) ; Mycophenolic Acid (HU9DX48N0T)
Language	English
Publishing date	2017-12
Publishing country	France
Document type	Clinical Trial ; Journal Article
ZDB-ID	196729-0
ISSN	2107-0180 ; 0398-7639 ; 0378-7966
ISSN (online)	2107-0180
ISSN	0398-7639 ; 0378-7966
DOI	10.1007/s13318-017-0420-3
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Article ; Online: How accurate and precise are limited sampling strategies in estimating exposure to mycophenolic acid in people with autoimmune disease?

Abd Rahman, Azrin N / Tett, Susan E / Staatz, Christine E

Clinical pharmacokinetics

2013 Volume 53, Issue 3, Page(s) 227–245

Abstract: Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h ... ...

Abstract	Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for maximum a posteriori (MAP) Bayesian analysis. Although mean bias was less when data were analysed using multiple linear regression, MAP Bayesian analysis is preferable because of its flexibility with respect to sample timing. Estimation of MPA AUC12 following EC-MPS administration using a limited sampling strategy with samples drawn within 3 h post-dose resulted in biased and imprecise results, likely due to a longer time to reach a peak MPA concentration (t max) with this formulation and more variable pharmacokinetic profiles. Inclusion of later sampling time points that capture enterohepatic recirculation and t max improved the predictive performance of strategies to predict EC-MPS exposure. Given the considerable pharmacokinetic variability associated with mycophenolate therapy, limited sampling strategies may potentially help in individualizing patient dosing. However, a compromise needs to be made between the predictive performance of the strategy and its clinical feasibility. An opportunity exists to combine research efforts globally to create an open-source database for MPA (AUC, concentrations and outcomes) that can be used and prospectively evaluated for AUC target-controlled dosing of MPA in autoimmune diseases.
MeSH term(s)	Adult ; Antibiotics, Antineoplastic/analysis ; Antibiotics, Antineoplastic/pharmacokinetics ; Autoimmune Diseases/metabolism ; Female ; Humans ; Male ; Middle Aged ; Mycophenolic Acid/analysis ; Mycophenolic Acid/pharmacokinetics ; Specimen Handling ; Young Adult
Chemical Substances	Antibiotics, Antineoplastic ; Mycophenolic Acid (HU9DX48N0T)
Language	English
Publishing date	2013-12-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-013-0124-z
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Article ; Online: Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease.

Abd Rahman, Azrin N / Tett, Susan E / Staatz, Christine E

Clinical pharmacokinetics

2013 Volume 52, Issue 5, Page(s) 303–331

Abstract: Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and ... ...

Abstract	Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and pharmacodynamics of mycophenolate in this population should assist the clinician with rational dosage decisions. This review aims to provide an overview of the published literature on the clinical pharmacokinetics of mycophenolate in autoimmune disease and a briefer summary of current pharmacodynamic knowledge, and to identify areas of potential future research in this field. A literature search was conducted using PubMed and EMBASE databases as well as bibliographies of relevant articles and 'on-line early' pages of key journals. Twenty-six pharmacokinetic/pharmacodynamic studies of mycophenolate in people with autoimmune disease were identified and appraised. Twenty-two of these studies used non-compartmental analysis techniques and four used population modelling methods to estimate mycophenolate pharmacokinetic parameters. Seven studies linked mycophenolate exposure to treatment outcomes. Only four studies measured free (unbound) as well as total mycophenolate exposure and only two studies characterised MPA disposition following enteric-coated mycophenolate sodium (EC-MPS) administration. Across all studies MPA displayed erratic and complex pharmacokinetics with substantial between-subject variability. Based on total drug measurement, the dose-normalised MPA area under the plasma concentration-time curve (AUC) from 0 to 12 h post-dose (AUC12) varied at least five- to ten-fold between subjects. Typical values for apparent oral clearance (CL/F) of MPA during nonlinear mixed-effects modelling ranged from 8.3 to 25.3 L/h. Patient renal function, serum albumin levels, sex, ethnicity, food intake, concurrent administration of interacting drugs such as antacids, metal-containing medications and proton pump inhibitors and polymorphisms in genes encoding uridine diphosphate glucuronosyltransferase were identified in some studies as having a significant influence on the pharmacokinetics of mycophenolate. Typical MPA CL/F values in autoimmune disease patients were generally slightly lower than values published previously in population pharmacokinetic studies involving renal allograft recipients, possibly because of usage of ciclosporin, poorer renal function or lower serum albumin levels in the renal transplant cohort. In a single crossover study involving ten subjects only, significantly higher MPA AUC12 and maximum MPA concentration (C max) and lower MPA CL/F were reported following EC-MPS administration compared to mycophenolate mofetil administration. MPA exposure correlated well with treatment efficacy in patients with autoimmune disease (response to treatment, active disease and disease markers); however the relationship between MPA exposure and adverse events (infectious episodes, haematological toxicity and gastrointestinal symptoms) was unclear. Further investigation is required in autoimmune diseases such as chronic plaque psoriasis and rheumatoid arthritis and following EC-MPS administration. The extent of within-subject variability in the pharmacokinetics of mycophenolate is largely unknown and potential covariate influences need to be confirmed in studies with large subject numbers. A relationship between MPA and MPA metabolite exposure and toxicity needs to be established. The contribution of pharmacogenetics to the pharmacokinetics and pharmacodynamics of mycophenolate warrants further investigation, as does the utility of therapeutic drug monitoring. Dosing to achieve a target MPA AUC12 >35 mg·h/L is likely to lead to better efficacy outcomes in patients with autoimmune disease (rather than just giving standard doses, which lead to a wide range of exposures). However, the relationship between mycophenolate exposure and toxicity requires further investigation to determine the upper end of a target AUC range.
MeSH term(s)	Area Under Curve ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/immunology ; Dose-Response Relationship, Drug ; Drug Monitoring ; Humans ; Immunosuppressive Agents/administration & dosage ; Immunosuppressive Agents/pharmacokinetics ; Immunosuppressive Agents/therapeutic use ; Models, Biological ; Mycophenolic Acid/administration & dosage ; Mycophenolic Acid/analogs & derivatives ; Mycophenolic Acid/pharmacokinetics ; Mycophenolic Acid/therapeutic use ; Nonlinear Dynamics ; Pharmacogenetics
Chemical Substances	Immunosuppressive Agents ; Mycophenolic Acid (HU9DX48N0T)
Language	English
Publishing date	2013-03-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-013-0039-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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