15 results on '"Page‐Sharp, Madhu"'
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2. The pharmacokinetic properties of artemether and lumefantrine in Malaysian patients with Plasmodium knowlesi malaria.
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Sugiarto, Sri Riyati, Singh, Balbir, Page‐Sharp, Madhu, Davis, Wendy A., Salman, Sam, Hii, King Ching, and Davis, Timothy M. E.
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MALARIA ,PLASMODIUM ,LIQUID chromatography-mass spectrometry ,PHARMACOKINETICS ,DRIED blood spot testing - Abstract
Aims: The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria. Methods: Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time‐points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl‐lumefantrine were measured using liquid chromatography‐mass spectrometry. Multi‐compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations. Results: Forty‐one participants (mean age 45 years, 66% males) were recruited. Artemether‐lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration–time curve (AUC0–∞) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto‐induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half‐life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria. Conclusion: The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes. [ABSTRACT FROM AUTHOR]
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- 2022
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3. A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.
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Hand, Robert M, Salman, Sam, Newall, Nelly, Vine, Julie, Page-Sharp, Madhu, Bowen, Asha C, Gray, Katherine, Baker, Amy, Kado, Joseph, Joseph, John, Marsh, Julie, Ramsay, James, Sika-Paotonu, Dianne, Batty, Kevin T, Manning, Laurens, and Carapetis, Jonathan
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RHEUMATIC heart disease ,ADOLESCENCE ,RHEUMATIC fever ,INTRAMUSCULAR injections ,PENICILLIN G ,CEFAZOLIN - Abstract
Background: Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD.Methods: We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data.Results: Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½.Conclusions: Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2019
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4. Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late‐onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes.
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Salman, Sam, Hibbert, Julie, Page‐Sharp, Madhu, Manning, Laurens, Simmer, Karen, Doherty, Dorota A., Patole, Sanjay, Batty, Kevin T., and Strunk, Tobias
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PHARMACOKINETICS ,ENTEROCOLITIS ,METABOLITES ,NEONATAL intensive care ,PHARMACOLOGY - Abstract
Aims: Infection‐induced inflammation is associated with adverse long‐term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late‐onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. Method: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg−1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg−1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. Results: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3–30.4) and birthweight of 689 g (370–1285). PTX was well tolerated and without treatment‐limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six‐fold difference in exposure between 24 and 35 weeks postmenstrual age. Conclusions: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants. A population pharmacokinetic model was developed to characterize the six‐fold range in exposure in the studied infants despite using a weight‐based dosing regimen for these critically ill preterm infants. [ABSTRACT FROM AUTHOR]
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- 2019
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5. Simultaneous determination of pentoxifylline, metabolites M1 (lisofylline), M4 and M5, and caffeine in plasma and dried blood spots for pharmacokinetic studies in preterm infants and neonates.
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Page-Sharp, Madhu, Strunk, Tobias, Salman, Sam, Hibbert, Julie, Patole, Sanjay K., Manning, Laurens, and Batty, Kevin T.
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PENTOXIFYLLINE , *METABOLITES , *PHARMACOKINETICS , *PHYSIOLOGICAL effects of caffeine , *DRIED blood spot testing , *BLOOD plasma - Abstract
Advances in bioanalytical methods are facilitating micro-volume and dried blood spot (DBS) analysis of drugs in biological matrices for pharmacokinetic studies in children and neonates. We sought to develop a UPLC–MS/MS assay for simultaneous measurement of caffeine, pentoxifylline (PTX) and three metabolites of PTX in both plasma and DBS. Caffeine, PTX, the metabolites M1 (lisofylline), M4 and M5, and the internal standards (caffeine-d 9 and PTX-d 6 ) were separated using a Waters Aquity T3 UPLC C 18 column and gradient mobile phase (water-methanol-formic acid). Retention times for caffeine, M5, M4, PTX and M1 were 1.6, 1.7, 1.9, 2.0 and 2.1 min, respectively, with a run time of 5 min. The precision (≤10%) and accuracy (≤15%) across the concentration range 0.1–50 mg/L for caffeine, PTX and the three metabolites in plasma and DBS were within accepted limits, as were the limits of quantification (100 μg/L for caffeine and 10 μg/L for PTX, M1, M4 and M5). Caffeine, PTX and the metabolites were stable in DBS for >34 days at room and refrigerated temperatures. Plasma and DBS samples were obtained from 24 preterm infants recruited into a clinical pharmacokinetic study of PTX. Paired analysis indicated that DBS concentrations were 9% lower than concurrent plasma concentrations for caffeine, 7% lower for PTX (consistent with the blood:plasma ratio) and 13% lower for M1 (lisofylline). The validated UPLC–MS/MS method is suitable for micro-volume plasma and DBS analysis of caffeine, PTX and its metabolites for pharmacokinetic studies in paediatric patients. [ABSTRACT FROM AUTHOR]
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- 2017
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6. Safety, tolerability and pharmacokinetic properties of coadministered azithromycin and piperaquine in pregnant Papua New Guinean women.
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Moore, Brioni R., Benjamin, John M., Auyeung, Siu On, Salman, Sam, Yadi, Gumul, Griffin, Suzanne, Page‐Sharp, Madhu, Batty, Kevin T., Siba, Peter M., Mueller, Ivo, Rogerson, Stephen J., and Davis, Timothy ME
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MALARIA treatment ,AZITHROMYCIN ,ANTIMALARIALS ,MALARIA in pregnancy ,PHARMACODYNAMICS ,PHARMACOKINETICS ,DRUG dosage - Abstract
Aims The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of coadministered azithromycin (AZI) and piperaquine (PQ) for treating malaria in pregnant Papua New Guinean women. Methods Thirty pregnant women (median age 22 years; 16-32 weeks' gestation) were given three daily doses of 1 g AZI plus 960 mg PQ tetraphosphate with detailed monitoring/blood sampling over 42 days. Plasma AZI and PQ were assayed using liquid chromatography-mass spectrometry and high-performance liquid chromatography, respectively. Pharmacokinetic analysis was by population-based compartmental models. Results The treatment was well tolerated. The median (interquartile range) increase in the rate-corrected electrocardiographic QT interval 4 h postdose [12 (6-26) ms
0 .5 ] was similar to that found in previous studies of AZI given in pregnancy with other partner drugs. Six women with asymptomatic malaria cleared their parasitaemias within 72 h. Two apararasitaemic women developed late uncomplicated Plasmodium falciparum infections on Days 42 and 83. Compared with previous pregnancy studies, the area under the concentration-time curve (AUC0-∞ ) for PQ [38818 (24354-52299) μg h l−1 ] was similar to published values but there was a 52% increase in relative bioavailability with each dose. The AUC0-∞ for AZI [46799 (43526-49462) μg h l−1 ] was at least as high as reported for higher-dose regimens, suggesting saturable absorption and/or concentration-dependent tissue uptake and clearance from the central compartment. Conclusions AZI-PQ appears to be well tolerated and safe in pregnancy. Based on the present/other data, total AZI doses higher than 3 g for the treatment and prevention of malaria may be unnecessary in pregnant women, while clearance of parasitaemia could improve the relative bioavailability of PQ. [ABSTRACT FROM AUTHOR]- Published
- 2016
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7. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.
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Senarathna, S M D K Ganga, Page-Sharp, Madhu, and Crowe, Andrew
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PROTEIN-drug interactions , *P-glycoprotein , *ANTIMALARIALS , *BIOCHEMICAL substrates , *DRUG absorption , *PERMEABILITY (Biology) - Abstract
The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. [ABSTRACT FROM AUTHOR]
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- 2016
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8. Use of quantitative pharmacology tools to improve malaria treatments.
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Davis, Timothy M. E., Salman, Sam, Moore, Brioni R., Manning, Laurens, Page-Sharp, Madhu, and Batty, Kevin T.
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MALARIA treatment ,PHARMACOKINETICS ,PHARMACODYNAMICS - Abstract
The use of pharmacokinetic (PK) and pharmacodynamic (PD) data to inform antimalarial treatment regimens has accelerated in the past few decades, due in no small part to the stimulus provided by progressive development of parasite resistance to most of the currently available drugs. An understanding of the disposition, interactions, efficacy and toxicity of the mainstay of contemporary antimalarial treatment, artemisinin combination therapy (ACT), has been facilitated by PK/PD studies which have been used to refine treatment regimens across the spectrum of disease, especially in special groups including young children and pregnant women. The present review highlights recent clinically-important examples of the ways in which these quantitative pharmacology tools have been applied to improve ACT, as well as 8-aminoquinoline use and the characterisation of novel antimalarial therapies such as the spiroindolones. [ABSTRACT FROM PUBLISHER]
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- 2016
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9. Continuous Infusions of Meropenem in Ambulatory Care: Clinical Efficacy, Safety and Stability.
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Manning, Laurens, Wright, Cameron, Ingram, Paul R., Whitmore, Timothy J., Heath, Christopher H., Manson, Ingrid, Page-Sharp, Madhu, Salman, Sam, Dyer, John, and Davis, Timothy M. E.
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INFUSION therapy ,DRUG administration ,OUTPATIENT medical care ,TREATMENT effectiveness ,ANTIBIOTICS ,ELASTOMERS - Abstract
Objectives: Concerns regarding the clinical impact of meropenem instability in continuous infusion (CI) devices may contribute to inconsistent uptake of this method of administration across outpatient parenteral antimicrobial therapy (OPAT) services. Methods: We retrospectively reviewed the clinical efficacy and safety of CIs of meropenem in two Australian tertiary hospitals and assessed its stability under simulated OPAT conditions including in elastomeric infusion devices containing 1% (2.4 g) or 2% (4.8 g) concentrations at either ‘room temperature’ or ‘cooled’ conditions. Infusate aliquots were assayed at different time-points over 24 hours. Results: Forty-one (82%) of 50 patients had clinical improvement or were cured. Adverse patient outcomes including hemato-, hepato- and nephrotoxicity were infrequent. Cooled infusers with 1% meropenem had a mean 24-hour recovery of 90.3%. Recoveries of 1% and 2% meropenem at room temperature and 2% under cooled conditions were 88%, 83% and 87%, respectively. Patients receiving 1% meropenem are likely to receive >95% of the maximum deliverable dose (MDD) over a 24-hour period whilst patients receiving 2% meropenem should receive 93% and 87% of the MDD under cooled and room temperature conditions, respectively. Conclusions: Meropenem infusers are likely to deliver ∼95% MDD and maintain effective plasma concentrations throughout the dosing period. These data reflect our local favourable clinical experience with meropenem CIs. [ABSTRACT FROM AUTHOR]
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- 2014
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10. Pharmacokinetic properties of the antimalarial combination therapy artemether–lumefantrine in normal-weight, overweight and obese healthy male adults.
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Sugiarto, Sri Riyati, Page-Sharp, Madhu, Drinkwater, Jocelyn J., Davis, Wendy A., Salman, Sam, and Davis, Timothy M.E.
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LIQUID chromatography-mass spectrometry , *PHARMACOKINETICS , *OBESITY , *BODY weight , *BODY mass index - Abstract
• Artemether–lumefantrine (AL) is a widely used combination antimalarial therapy. • Its component drugs are lipid-soluble with potential pharmacokinetic implications. • These include lower plasma concentrations in overweight and obesity. • AL disposition was not significantly different across body mass index categories. • Recommended AL treatment doses can be given regardless of body weight. The component drugs in the widely used antimalarial artemisinin combination therapy artemether–lumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to subtherapeutic concentrations and consequent treatment failure in overweight/obese individuals with malaria. The aim of this study was to investigate the pharmacokinetic properties of artemether, lumefantrine and their active metabolites dihydroartemisinin and desbutyl-lumefantrine in 16 normal-weight, overweight and obese healthy male volunteers [body mass index (BMI) categories ≤25 kg/m², >25–≤30 kg/m² and >30 kg/m², respectively; absolute range 19.3–37.2 kg/m²]. Participants received the conventional six doses of artemether–lumefantrine over 3 days, each dose comprising 80 mg artemether plus 480 mg lumefantrine administered with 6.7 g fat, and blood samples were collected at pre-specified time-points over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatography-mass spectrometry and included in multi-compartmental population pharmacokinetic models. There was a non-significant trend to a lower area under the plasma concentration–time curve with a higher body weight or BMI for dihydroartemisinin and especially artemether which was attenuated when normalized for mg/kg dose, but this relationship was not evident in the case of the more lipophilic lumefantrine and its metabolite desbutyl-lumefantrine. Simulated Day 7 plasma lumefantrine concentrations were >200 µg/L (the threshold at which Plasmodium falciparum recrudescences are minimized) in all participants. These results indicate that there is no need for artemether–lumefantrine dose modification in overweight and obese patients with malaria. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Simultaneous determination of primaquine and carboxyprimaquine in plasma using solid phase extraction and LC–MS assay
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Page-Sharp, Madhu, Ilett, Kenneth F., Betuela, Inoni, Davis, Timothy M.E., and Batty, Kevin T.
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PRIMAQUINE , *BLOOD plasma , *SOLID phase extraction , *LIQUID chromatography-mass spectrometry , *PHARMACOKINETICS , *METABOLITES - Abstract
Abstract: Sensitive bioanalytical methods are required for pharmacokinetic studies in children, due to the small volume and modest number of samples that can be obtained. We sought to develop a LC–MS assay for primaquine and its active metabolite, carboxyprimaquine, following simultaneous, solid phase extraction of both analytes from human plasma. The analysis was conducted on a single-quad LC–MS system (Shimadzu Model 2020) in ESI+ mode, with quantitation by selected ion monitoring. Primaquine, carboxyprimaquine and 8-aminoquinoline (internal standard) were separated using a mobile phase of 80:20 methanol:water with 0.1% (v/v) formic acid and a Luna C18 HPLC column, at ambient temperature. Solid phase extraction of the analytes from plasma (0.5mL) was achieved with Oasis® HLB cartridges. The retention times for primaquine, 8-aminoquinoline and carboxyprimaquine were 3.3, 5.7 and 8.5min, respectively. The calibration curve range (2–1500μg/L) was appropriate for the limits of quantification and detection for primaquine (2μg/L and 1μg/L, respectively) and carboxyprimaquine (2.5μg/L and 1μg/L) and the anticipated plasma concentrations of the analytes. Intra- and inter-day precision for both primaquine and carboxyprimaquine was <10% across the concentration range 5–1000μg/L. Accuracy for both analytes was <15% (5–500μg/L). This validated LC–MS method with solid phase extraction facilitates the simultaneous analysis of primaquine and carboxyprimaquine from small volumes of human plasma, with run time <10min, recovery >85% and sensitivity of 1–2μg/L. [Copyright &y& Elsevier]
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- 2012
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12. Short-course, high-dose primaquine regimens for the treatment of liver-stage vivax malaria in children.
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Moore, Brioni R., Salman, Sam, Tobe, Roselyn, Benjamin, John, Yadi, Gumul, Kasian, Bernadine, Laman, Moses, Robinson, Leanne J., Page-Sharp, Madhu, Betuela, Inoni, Batty, Kevin T., Manning, Laurens, Mueller, Ivo, and Davis, Timothy M.E.
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MALARIA , *PRIMAQUINE , *GLUCOSE-6-phosphate dehydrogenase , *CHILD patients , *PATIENT compliance - Abstract
• A novel 3.5-day primaquine (PQ) regimen was well tolerated and relatively safe. • Supervised doses given with food ameliorated the gastrointestinal adverse effects. • Pharmacokinetic data support the ultra-short PQ regimens with a twice-daily dosing. • Short-course PQ regimens will likely improve treatment acceptability and adherence. To assess the pharmacokinetics, safety, and tolerability of two high-dose, short-course primaquine (PQ) regimens compared with standard care in children with Plasmodium vivax infections. We performed an open-label pediatric dose-escalation study in Madang, Papua New Guinea (Clinicaltrials.gov NCT02364583). Children aged 5-10 years with confirmed blood-stage vivax malaria and normal glucose-6-phosphate dehydrogenase activity were allocated to one of three PQ treatment regimens in a stepwise design (group A: 0.5 mg/kg once daily for 14 days, group B: 1 mg/kg once daily for 7 days, and group C: 1 mg/kg twice daily for 3.5-days). The study assessments were completed at each treatment time point and fortnightly for 2 months after PQ administration. Between August 2013 and May 2018, 707 children were screened and 73 met the eligibility criteria (15, 40, and 16 allocated to groups A, B, and C, respectively). All children completed the study procedures. The three regimens were safe and generally well tolerated. The pharmacokinetic analysis indicated that an additional weight adjustment of the conventionally recommended milligram per kilogram PQ doses is not necessary to ensure the therapeutic plasma concentrations in pediatric patients. A novel, ultra-short 3.5-day PQ regimen has potential benefits for improving the treatment outcomes in children with vivax malaria that warrants further investigation in a large-scale clinical trial. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling.
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Salman, Sam, Baiwog, Francesca, Page-Sharp, Madhu, Kose, Kay, Karunajeewa, Harin A., Mueller, Ivo, Rogerson, Stephen J., Siba, Peter M., Ilett, Kenneth F., and Davis, Timothy M.E.
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ANTIMALARIALS , *DRUG dosage , *PHARMACOKINETICS , *CHLOROQUINE , *PREGNANCY complications , *MATHEMATICAL models - Abstract
Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration–time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Investigation of reproductive toxicity of piperaquine in mice
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Batty, Kevin T., Moore, Brioni R., Stirling, Verity, Ilett, Kenneth F., Page-Sharp, Madhu, Shilkin, Keith B., Mueller, Ivo, Rogerson, Stephen J., Karunajeewa, Harin A., and Davis, Timothy M.E.
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REPRODUCTIVE toxicology , *ANTIMALARIALS , *LABORATORY mice , *PHARMACOKINETICS , *PREGNANCY in animals , *HISTOPATHOLOGY , *HEMATOLOGY , *CLINICAL biochemistry - Abstract
Abstract: Reproductive toxicity data for the antimalarial drug piperaquine (PQ) were obtained in pregnant mice (F0) and their offspring (F1 and F2). PQ phosphate (0–300mg/kg/day) was given to pregnant Swiss mice from gestational days 14–18. Two F1 pups from each litter (one male and one female) proceeded to maturity and were mated within dose groups. Biochemical and haematological indices were determined, and liver and kidney histopathology was assessed in F1 and F2 mice at 4 weeks. There were no significant dose-related adverse effects, but leucocytes were mildly elevated (F1 and F2 mice) and serum albumin was reduced (F1 only) in the 300mg/kg/day group. Low plasma PQ concentrations were detected in F1 mice at 4 and 8 weeks. Although we found no significant PQ toxicity, clinical data are lacking and monitoring of women and their infants for biochemical and haematological adverse effects is recommended when PQ is used in pregnancy. [Copyright &y& Elsevier]
- Published
- 2010
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15. Toxicology and pharmacokinetics of piperaquine in mice
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Batty, Kevin T., Moore, Brioni R., Stirling, Verity, Ilett, Kenneth F., Page-Sharp, Madhu, Shilkin, Keith B., Mueller, Ivo, Karunajeewa, Harin A., and Davis, Timothy M.E.
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ANTIMALARIALS , *MICE , *WEIGHT loss , *HEPATOTOXICOLOGY - Abstract
Abstract: Pharmacokinetic and toxicological data for piperaquine (PQ) – a bisquinoline antimalarial drug – are limited, despite strong evidence of clinical efficacy. Our aim was to conduct a detailed toxicological investigation of PQ in Swiss mice. The study comprised three phases: (i) oral PQ phosphate (PQP) at doses ranging from 0 to 600mg/(kgday) for 5 days. Pathology tests included haematological and biochemical indices, and histopathology of the liver, heart and kidneys. (ii) PQP doses of 0–300mg/(kgday) for 12 days and pathology tests as described. (iii) Pharmacokinetic parameters determined from mice given 100mg/(kgday) PQP for 5 days. Blood was harvested from mice over 56 days and plasma analysed by HPLC. Mice given low doses of PQ had stable, normal body and organ weights. Weight loss was observed in mice given high doses and was accompanied by increased liver and kidney weights. Principal haematological effects were modest fluctuations in total white cells and neutrophils; biochemical effects were elevated ALT and low albumin in high-dose groups. Liver histopathology revealed minor cytoplasmic and inflammatory effects. PQ treatment did not affect heart muscle but minor renal changes were observed at high doses. Pharmacokinetic parameters were consistent with previous studies: t ½, CL and V were 16 days, 1.36L/(hkg) and 756L/kg, respectively. PQ may cause minor hepatotoxicity and renal tubular cell damage, and adversely affect selected haematological indices, as demonstrated at cumulative doses approximately 50 times those recommended in humans. Significant effects in humans will likely be infrequent and dose-related. [Copyright &y& Elsevier]
- Published
- 2008
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