Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine

ABSTRACT Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.)

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Drug Interactions Between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine

10.1101/351684 ◽

2018 ◽

Author(s):

Stephen I Walimbwa ◽

Mohammed Lamorde ◽

Catriona Waitt ◽

Julian Kaboggoza ◽

Laura Else ◽

...

Keyword(s):

Maximum Concentration ◽

Geometric Mean ◽

Compartmental Analysis ◽

Sub Saharan Africa ◽

Pharmacokinetic Studies ◽

Serious Adverse Events ◽

Time Curve ◽

Once Daily ◽

Trough Concentrations ◽

Sub Saharan

ABSTRACTAcross sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for ARM, DHA, LF and DBL nor significantly alter AUC for ARS, DHA, AQ and DEAQ. Co-administration of dolutegravir with AL resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with AS-AQ resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. Study drugs were well-tolerated with no serious adverse events. Standard doses of artmether-lumefantrine and artesunate-amodiaquine should be used in patients receiving DTG. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and DTG exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above DTG target concentrations of 64ng/mL.

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Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01468-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2852-2856 ◽

Cited By ~ 104

Author(s):

Larissa A. Wenning ◽

William D. Hanley ◽

Diana M. Brainard ◽

Amelia S. Petry ◽

Kalyan Ghosh ◽

...

Keyword(s):

Geometric Mean ◽

Pharmacokinetic Studies ◽

Strand Transfer ◽

Time Curve ◽

Metabolizing Enzymes ◽

Potent Inducer ◽

Once Daily ◽

Immunodeficiency Virus ◽

Transfer Inhibitor ◽

Trough Concentrations

ABSTRACT Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg raltegravir twice daily compared to 400-mg raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma raltegravir concentration determined 12 h postdose (C 12), area under the concentration-time curve from 0 h to ∞ (AUC0-∞), and maximum concentration of drug in plasma (C max) (400-mg raltegravir plus rifampin/400-mg raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for raltegravir C 12, AUC0-12, and C max (800-mg raltegravir plus rifampin/400-mg raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on raltegravir exposure (AUC0-12) but does not overcome the effect of rifampin on raltegravir trough concentrations (C 12). Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used, since raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.

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Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01564-09 ◽

2010 ◽

Vol 54 (7) ◽

pp. 2775-2780 ◽

Cited By ~ 6

Author(s):

Gaik H. Soon ◽

Ping Shen ◽

Eu-Leong Yong ◽

Paul Pham ◽

Charles Flexner ◽

...

Keyword(s):

Healthy Volunteers ◽

Half Life ◽

Geometric Mean ◽

Wild Type Virus ◽

Type Virus ◽

Wild Type ◽

Time Curve ◽

Once Daily ◽

Drug Concentrations ◽

Trough Concentrations

ABSTRACT Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC50) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC0-24) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC0-24 (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

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Short-Course Artesunate Treatment of Uncomplicated Plasmodium falciparum Malaria in Gabon

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.3.901-904.2003 ◽

2003 ◽

Vol 47 (3) ◽

pp. 901-904 ◽

Cited By ~ 21

Author(s):

Steffen Borrmann ◽

Ayola A. Adegnika ◽

Michel A. Missinou ◽

Ronald K. Binder ◽

Saadou Issifou ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Body Weight ◽

Falciparum Malaria ◽

Geometric Mean ◽

Plasmodium Falciparum Malaria ◽

Sub Saharan Africa ◽

Once Daily ◽

Systematic Assessment ◽

Malaria Burden ◽

Sub Saharan

ABSTRACT Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated Plasmodium falciparum malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well tolerated, and no severe adverse event was reported. Parasite elimination was rapid and was achieved in all patients within ≤72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.

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P78 Pharmacokinetics of intravenous and intranasal nalbuphine in infants

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.116 ◽

2019 ◽

Vol 104 (6) ◽

pp. e49.2-e49

Author(s):

M Pfiffner ◽

V Gotta ◽

E Berger-Olah ◽

M Pfister ◽

P Vonbach

Keyword(s):

Maximum Concentration ◽

Opioid Analgesic ◽

Wilcoxon Test ◽

Noncompartmental Analysis ◽

Open Label ◽

Post Dose ◽

Time Curve ◽

Acute Setting ◽

Non Invasive ◽

Concentration Time

BackgroundNalbuphine is a mixed agonist-antagonist opioid analgesic agent frequently used in paediatrics, and licensed for parenteral use only. Intranasal delivery could be a safe, effective and non-invasive alternative, especially in infants in the acute setting. However, pharmacokinetic (PK) data for this route of administration is completely lacking. The aim of this study was to assess PK of nalbuphine in infants 1–3 months after single intravenous (0.05 mg/kg) and intranasal (0.1 mg/kg) application, respectively.MethodsWe conducted a prospective, single centre, open-label pharmacokinetic study in infants 1–3 months undergoing sepsis workup in the emergency unit. Included infants received alternating nalbuphine as 0.05 mg/kg intravenous bolus or as 0.1 mg/kg intranasal spray. PK samples were taken at 3 pre-defined time points (15, 30 and max. 240 min post-dose before discharge). Area under the concentration-time curve (AUC0-Tlast, and AUC0-infinity for i.v.) was calculated using noncompartmental analysis and was compared between groups using Wilcoxon test. Further parameters derived included maximum concentration (Cmax), time of maximum concentration (Tmax for i.n.) and terminal half-life (t1/2).ResultsA total of 31 patients were included in the analysis. Median age was 55 days [interquartile range 38–63] in the intranasal (N=20) and 42 [37–76] days in the iv group (N=11). Median AUC0-Tlast was 7.6 (5.4–10.4) mcg*h/L following intranasal versus 7.9 (6.0–14.7) mcg*h/L for iv administration (p=0.46). AUC0-Tlast (i.v.) covered 80 [68–83]% of AUC0-infinity. Median Cmax was 4.5 [3.5–5.6] mcg/L (i.n.) versus 6.5 [5.3–15.9] mcg/L (i.v.) (p=0.014), t1/22.4 [1.3–2.8] h (i.n.) versus 1.3 [1.1–1.5] h (i.v.) (p=0.021). Tmax occurred 37 [32–65] min after intranasal administration.ConclusionThis first PK study of intranasal nalbuphine in infants suggests that 0.1 mg/kg i.n. dosing provides similar exposure as 0.05 mg/kg i.v. in infants in terms of AUC, and hence intranasal bioavailability close to 50%.Disclosure(s)Nothing to disclose

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Reduced Parasite Burden in Children with Falciparum Malaria and Bacteremia Coinfections: Role of Mediators of Inflammation

Mediators of Inflammation ◽

10.1155/2016/4286576 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 9

Author(s):

Gregory C. Davenport ◽

James B. Hittner ◽

Vincent Otieno ◽

Zachary Karim ◽

Harshini Mukundan ◽

...

Keyword(s):

Geometric Mean ◽

Parasite Burden ◽

Sub Saharan Africa ◽

Mediation Model ◽

Multiple Mediation ◽

Mediators Of Inflammation ◽

Threatening Condition ◽

Life Threatening ◽

Sub Saharan

Bacteremia and malaria coinfection is a common and life-threatening condition in children residing in sub-Saharan Africa. We previously showed that coinfection with Gram negative (G[−]) enteric Bacilli andPlasmodium falciparum(Pf[+]) was associated with reduced high-density parasitemia (HDP, >10,000 parasites/μL), enhanced respiratory distress, and severe anemia. Since inflammatory mediators are largely unexplored in such coinfections, circulating cytokines were determined in four groups of children (n=206, aged <3 yrs): healthy;Pf[+] alone; G[−] coinfected; and G[+] coinfected.Staphylococcus aureusand non-TyphiSalmonellawere the most frequently isolated G[+] and G[−] organisms, respectively. Coinfected children, particularly those with G[−] pathogens, had lower parasite burden (peripheral and geometric mean parasitemia and HDP). In addition, both coinfected groups had increased IL-4, IL-5, IL-7, IL-12, IL-15, IL-17, IFN-γ, and IFN-αand decreased TNF-αrelative to malaria alone. Children with G[−] coinfection had higher IL-1βand IL-1Ra and lower IL-10 than thePf[+] group and higher IFN-γthan the G[+] group. To determine how the immune response to malaria regulates parasitemia, cytokine production was investigated with a multiple mediation model. Cytokines with the greatest mediational impact on parasitemia were IL-4, IL-10, IL-12, and IFN-γ. Results here suggest that enhanced immune activation, especially in G[−] coinfected children, acts to reduce malaria parasite burden.

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Follow-Up of Elevated Blood Lead Levels and Sources in a Cohort of Children in Benin

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17228689 ◽

2020 ◽

Vol 17 (22) ◽

pp. 8689

Author(s):

Shukrullah Ahmadi ◽

Barbara Le Bot ◽

Roméo Zoumenou ◽

Séverine Durand ◽

Nadine Fiévet ◽

...

Keyword(s):

Lead Exposure ◽

Inductively Coupled Plasma ◽

Geometric Mean ◽

Blood Lead ◽

Sub Saharan Africa ◽

Blood Lead Levels ◽

Inductively Coupled ◽

Potential Sources ◽

Lead Levels ◽

Sub Saharan

Lead exposure is associated with poor cognitive development in children. Very few studies in sub-Saharan Africa (SSA) have studied blood lead levels (BLLs) and non-gasoline sources of exposure in children. Data from a birth cohort in Benin (2011–2013) suggested that 58% of 1-year-old children had BLLs > 50 ug/L. We aimed to investigate the prevalence of elevated BLLs (>50 µg/L and >100 µg /L) among 425 of these children at 6 years of age in 2016–2018 and to compare BLLs between age 1 and 6 years, and study sources of lead at age 6 years. BLLs were analysed by inductively coupled plasma mass spectrometry. Multiple linear regression and quantile regressions were used to study potential sources of lead. The prevalence of BLLs > 50 µg/L in children was 59.5% (Geometric Mean (GM) 56.4 µg/L, 95% CI: 54.1–58.7) at 6 years of age compared to 54.8% (GM 56.5 µg/L, 95% CI: 53.4–59.6) at 1 year of age. The prevalence of children with BLLs > 100 µg/L decreased from 14.4% at 1 year of age to 8.2% at 6 years of age. After adjustment for all other covariates, consumption of peanuts more than once per month was significantly associated with a 22.0% (95% CI: 4.6, 42.5) increment in BLLs at age 6 years compared with no consumption. Consumption of bushmeat killed by lead bullets at age 6 years was associated with an increase in the higher percentiles of BLLs (P75) compared with the absence of this source. Other potential sources of lead associated with BLLs with marginal significance were consumption of rice, paternal occupational exposure, and the presence of activity with the potential use of lead. This prospective cohort confirms the persistently high prevalence of elevated BLLs in children residing in a rural region in the south of Benin, as well as the presence of multiple and continuous sources of lead. These results highlight the need for prevention programs to reduce and eliminate lead exposure in children.

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Once-Daily Dosing in Dogs Optimizes Daptomycin Safety

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.11.2948-2953.2000 ◽

2000 ◽

Vol 44 (11) ◽

pp. 2948-2953 ◽

Cited By ~ 142

Author(s):

F. B. Oleson ◽

C. L. Berman ◽

J. B. Kirkpatrick ◽

K. S. Regan ◽

J.-J. Lai ◽

...

Keyword(s):

Skeletal Muscle ◽

Maximum Concentration ◽

Time Curve ◽

Once Daily ◽

Gram Positive Bacteria ◽

Concentration Time ◽

Serum Creatine Phosphokinase ◽

Lower Maximum ◽

Resistant Strains ◽

Lipopeptide Antibiotic

ABSTRACT Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.

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Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.11.4328-4331.2004 ◽

2004 ◽

Vol 48 (11) ◽

pp. 4328-4331 ◽

Cited By ~ 42

Author(s):

Robert DiCenzo ◽

Derick Peterson ◽

Kim Cruttenden ◽

Gene Morse ◽

Garret Riggs ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Valproic Acid ◽

Geometric Mean ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Blood Samples ◽

Immunodeficiency Virus ◽

Before And After ◽

Trough Concentrations ◽

Hiv 1

ABSTRACT Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

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Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00862-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 6252-6259 ◽

Cited By ~ 28

Author(s):

John S. Bradley ◽

Jon Armstrong ◽

Antonio Arrieta ◽

Raafat Bishai ◽

Shampa Das ◽

...

Keyword(s):

Single Dose ◽

Phase I ◽

Pediatric Patients ◽

Geometric Mean ◽

Open Label ◽

Serious Adverse Events ◽

Time Curve ◽

Age Cohorts ◽

Concentration Time ◽

Systemic Antibiotic Therapy

ABSTRACTThis study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0–∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)

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