30 results on '"Kokki, Hannu"'
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2. Maturation of Oxycodone Pharmacokinetics in Neonates and Infants: a Population Pharmacokinetic Model of Three Clinical Trials
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Välitalo, Pyry, Kokki, Merja, Ranta, Veli-Pekka, Olkkola, Klaus T., Hooker, Andrew C., and Kokki, Hannu
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- 2017
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3. Absorption of different oral dosage forms of oxycodone in the elderly: a cross-over clinical trial in patients undergoing cystoscopy
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Kokki, Merja, Välitalo, Pyry, Rasanen, Ilpo, Aaltomaa, Sirpa, Ojanperä, Ilkka, Eskelinen, Matti, and Kokki, Hannu
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- 2012
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4. Does coronary artery bypass surgery affect metoprolol bioavailability
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Valtola, Antti, Kokki, Hannu, Gergov, Merja, Ojanperä, Ilkka, Ranta, Veli-Pekka, and Hakala, Tapio
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- 2007
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5. Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage – a pilot study
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Soppi, Ville, Kokki, Hannu, Koivisto, Timo, Lehtonen, Marko, Helin-Tanninen, Minna, Lehtola, Sanna, and Rinne, Jaakko
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- 2007
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6. Population pharmacokinetics of oxycodone: Premature neonates to adults.
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Morse, James D, Sundermann, Milan, Hannam, Jacqueline A, Kokki, Hannu, Kokki, Merja, Anderson, Brian J, and Goobie, Susan
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ADULTS ,OXYCODONE ,ADIPOSE tissues ,NEWBORN infants ,BUCCAL administration - Abstract
Background: Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified. Methods: Pooled oxycodone time‐concentration profiles were available from preterm neonates to adults. Data from intravenous, intramuscular, buccal, and epidural formulations were analyzed using nonlinear mixed‐effects models. Normal fat mass was used to determine the influence of fat on oxycodone pharmacokinetics. Theory‐based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A maturation function described the increase in clearance in neonates and infants. Results: There were 237 subjects (24 weeks postmenstrual age to 75 years; 0.44–110 kg) providing 1317 plasma concentrations. A three‐compartment model with first‐order elimination best described oxycodone disposition. Population parameter estimates were clearance (CL) 48.6 L.h−1.70 kg−1 (CV 71%); intercompartmental clearances (Q2) 220 L.h−1.70 kg−1 (CV 64%); Q3 1.45 L.h−1.70 kg−1; volume of distribution in the central compartment (V1) 98.2 L.70 kg−1 (CV 76%); rapidly equilibrating peripheral compartment (V2) 90.1 L. 70 kg−1 (CV 76%); slow equilibrating peripheral compartment (V3) 28.9 L.70 kg−1. Total body weight was the best size descriptor for clearances and volumes. Absorption halftimes (TABS) were: 1.1 minutes for intramuscular, 70 minutes for epidural, 82 minutes for nasogastric, and 159.6 minutes for buccal administration routes. The relative bioavailability after nasogastric administration was 0.673 with a lag time of 8.7 minutes. Conclusions: Clearance matured with age; 8% of the typical adult value at 24 weeks postmenstrual age, 33% in a term neonate and reached 90% of the adult clearance value by the end of the first year of life. Allometric scaling using total body weight was the better size descriptor of oxycodone clearance than fat‐free mass. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Oxycodone target concentration dosing for acute pain in children.
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Morse, James D, Hannam, Jacqueline A, Anderson, Brian J, Kokki, Hannu, and Kokki, Merja
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OXYCODONE ,ADULTS ,RESPIRATORY insufficiency ,PAIN ,NEWBORN infants ,PHARMACOKINETICS - Abstract
Background: Oxycodone pharmacokinetics have been described in premature neonates through to obese adults. Covariate influences have been accounted for using allometry (size) and maturation of oxycodone clearance with age. The target concentration is dependent on pain intensity that may differ over pain duration or between individuals. Methods: We assumed a target concentration of 35 mcg.L−1 (acceptable range ±20%) to be associated with adequate analgesia without increased risk of adverse effects from respiratory depression. Pharmacokinetic simulation was used to estimate dose in neonates through to obese adults given intravenous or parenteral oxycodone. Results: There were 84% of simulated oxycodone concentrations within the acceptable range during maintenance dosing. Variability around the simulated target concentration decreased with age. The maturation of oxycodone clearance is reflected in changes to context‐sensitive halftime where clearance is immature in neonates compared with older children and adults. The intravenous loading and maintenance doses for a typical 5‐year‐old child are 100 mcg.kg−1 and 33 mcg.kg−1.h−1. In a typical adult, the loading dose is 100 mcg.kg−1 and maintenance dose 23 mcg.kg−1.h−1. Conclusion: Simulation was used to suggest loading and maintenance doses to attain an oxycodone concentration of 35 mcg.L−1 predicted in adults. Although the covariates age and weight contribute 92% variability for clearance, there remains variability accounting for 16% of concentrations outside the target range. Duration of analgesic effect after ceasing infusion is anticipated to be longer in neonates where context‐sensitive halftime is greater than older children and adults. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection.
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Hakomäki, Henriikka, Kokki, Hannu, Lehtonen, Marko, Ranta, Veli-Pekka, Räsänen, Juha, Voipio, Hanna-Marja, and Kokki, Merja
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INTRAVENOUS injections , *OPIOID abuse , *BUPRENORPHINE , *PHARMACOKINETICS , *PREGNANT women , *SHEEP - Abstract
Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 µg/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 µg/L and 0.04 µg/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum-maximum), were Cmax 4.31 µg/L (1.93-15.5), AUCinf 2.89 h*µg/L (1.72-40.2), CL 3.39 L/h/kg (0.25-6.02), terminal t½ 1.75 h (1.07-31.0), Vss 8.04 L/kg (1.05-49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half-lives for six subjects, and a wide between-subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans. [ABSTRACT FROM AUTHOR]
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- 2021
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9. Bioavailability of oxycodone by mouth in coronary artery bypass surgery patients - a randomized trial.
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Valtola, Antti, Morse, James D., Florkiewicz, Pawel, Hautajärvi, Heidi, Lahtinen, Pasi, Musialowicz, Tadeusz, Anderson, Brian J., Ranta, Veli-Pekka, and Kokki, Hannu
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BIOAVAILABILITY ,OXYCODONE ,CORONARY artery bypass ,RANDOMIZED controlled trials ,PHARMACOKINETICS - Abstract
Objective: Pain after coronary artery by-pass (CAB) surgery is severe. Analgesic administration by mouth is unreliable until after gastrointestinal function has recovered. We evaluated the bioavailability of oxycodone co-administered with naloxone by mouth in patients after CAB surgery using either a conventional extracorporeal circulation (CECC) or off-pump surgery (OPCAB). Methods: Twenty-four patients, 50-73 years, 12 with CECC and 12 with OPCAB, were administered a 10/5mg oxycodone-naloxone controlled-release tablet by mouth on the preoperative day and for the first seven postoperative days (PODs) thereafter. Blood samples were collected up to 24 h after the preoperative administration, and then randomly either on POD1 and POD3 or on POD2 and POD4. The oxycodone concentration in plasma was analyzed using liquid chromatography-mass spectrometry. Results: On POD1 oxycodone absorption was markedly delayed in five of six patients after CECC and in all six patients after OPCAB surgery; median of tmax after CECC 630 [range 270-1420] minutes and after OPCAB 1020 [720-1410] minutes, compared to median of 120-315 min preoperatively and on POD2-POD4. The carry-over corrected AUC
0-24 values on the PODs did not differ from the preoperative values, but were higher on POD3 compared with POD1 in both CECC and OPCAB groups. The rate and extent of oxycodone absorption equaled preoperative values on POD2 and onwards in patients with CAB surgery. Conclusions: Bioavailability of oxycodone by mouth was similar after CAB surgery via CECC or having OPCAB. Data indicate that POD2 is an appropriate time to start oxycodone administration by mouth after CAB surgery. [ABSTRACT FROM AUTHOR]- Published
- 2020
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10. Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions.
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Rytkönen, Jaana, Ranta, Veli‐Pekka, Kokki, Merja, Kokki, Hannu, Hautajärvi, Heidi, Rinne, Valtteri, and Heikkinen, Aki T.
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HYDROCODONE ,CYTOCHROME P-450 ,OXYCODONE ,SIMULATION methods & models ,NONOPIOID analgesics ,QUINIDINE ,KETOCONAZOLE - Abstract
Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5‐fold error for oxycodone, within 1.8‐fold and 1.3–4.5‐fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5‐fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co‐administered with oxycodone. [ABSTRACT FROM AUTHOR]
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- 2020
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11. Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe.
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Kinnunen, Mari, Kokki, Hannu, Hautajärvi, Heidi, Lantto, Juulia, Räsänen, Juha, Voipio, Hanna‐Marja, and Kokki, Merja
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CENTRAL nervous system , *EPIDURAL space , *CEREBROSPINAL fluid , *OXYCODONE , *SPINAL cord , *EWES - Abstract
The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg−1 bolus followed by continuous infusion of 0.05 mg·kg−1·h−1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg−1 bolus followed by a 0.2 mg·kg−1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL−1 after infusion and 0.4 and 1.1 ng·mL−1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4‐8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia. [ABSTRACT FROM AUTHOR]
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- 2019
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12. Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy—A randomised, double blind, active control, double‐dummy clinical comparison with intravenous administration.
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Piirainen, Panu, Kokki, Hannu, Anderson, Brian, Hannam, Jacqueline, Hautajärvi, Heidi, Ranta, Veli‐Pekka, and Kokki, Merja
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CEREBROSPINAL fluid examination , *NONOPIOID analgesics , *FENTANYL , *INTRAVENOUS therapy , *OXYCODONE , *PAIN management , *EPIDURAL space , *LAPAROSCOPY - Abstract
Aims: Early pain after laparoscopy is often severe. Oxycodone is a feasible analgesic option after laparoscopy, but there are sparse data on epidural administration. The aim was to evaluate the analgesic efficacy and pharmacokinetics of a single dose of epidural oxycodone as a part of multimodal analgesia after gynaecological laparoscopy. Methods: Women (n = 60), aged 23–71 years, undergoing elective gynaecological laparoscopy, were administrated either epidural oxycodone 0.1 mg kg−1 and intravenous (i.v.) saline (EPI‐group n = 31), or epidural saline and i.v. oxycodone 0.1 mg kg−1 (IV‐group = 29) in a randomised, double blind, active control, double dummy clinical trial. A pharmacokinetic model was developed using population modelling of plasma and cerebrospinal fluid (CSF) concentrations obtained in these patients and data of 2 published studies. The primary outcome was the amount of i.v. fentanyl for rescue analgesia during the first 4 hours. Results: Twenty of the 31 patients in the EPI‐group and 26 of the 29 patients in the IV‐group needed i.v. fentanyl for rescue analgesia, P =.021. The median (interquartile range) number of fentanyl doses were 1.0 (1.0–3.0) in the EPI‐group and 2.5 (1.0–4.0) doses in the IV‐group, P =.008. Plasma concentrations were similar, but CSF concentrations were 100‐fold higher in the EPI‐group. The population model indicated that 60% of oxycodone injected into the epidural space enters into CSF and 40% is absorbed into the systemic circulation. Conclusions: The data support superiority of epidural administration of oxycodone compared to i.v. administration during the first hours after laparoscopic surgery. This is likely to be based on enhanced permeation into the central nervous system after epidural administration. [ABSTRACT FROM AUTHOR]
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- 2019
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13. Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone.
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Kinnunen, Mari, Piirainen, Panu, Kokki, Hannu, Lammi, Pauliina, and Kokki, Merja
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OXYCODONE ,PHARMACOKINETICS ,CYTOCHROME P-450 ,DRUG interactions ,DRUG administration ,PHARMACODYNAMICS - Abstract
Global oxycodone consumption has increased sharply during the last two decades, and, in 2008, oxycodone consumption surpassed that of morphine. As oxycodone was synthesized in 1916 and taken to clinical use a year later, it has not undergone the same approval process required by today's standards. Most of the basic oxycodone pharmacokinetic (PK) data are from the 1990s and from academic research; however, a lot of additional data have been published over the last 10 years. In this review, we describe the latest oxycodone data on special populations, including neonates, children, pregnant and lactating women, and the elderly. A lot of important drug interaction data have been published that must also be taken into account when oxycodone is used concomitantly with cytochrome P450 (CYP) 3A inducers and inhibitors and/or CYP2D6 inhibitors. In addition, we gathered data on abuse-deterrent oxycodone formulations, and the PK of alternate administration routes, i.e. transmucosal and epidural, are also described. [ABSTRACT FROM AUTHOR]
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- 2019
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14. Oxycodone pharmacokinetics and fetal exposure after intravenous or epidural administration to the ewe.
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Kinnunen, Mari, Kokki, Hannu, Hautajärvi, Heidi, Huhta, Heikki, Ranta, Veli‐Pekka, Räsänen, Juha, Voipio, Hanna‐Marja, Kokki, Merja, Ranta, Veli-Pekka, and Voipio, Hanna-Marja
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SHEEP breeding , *OXYCODONE , *PREGNANCY in animals , *PHARMACOKINETICS , *BLOOD sampling , *CATHETERS , *METABOLISM in the fetus , *ANALGESICS , *ANIMALS , *CORD blood , *INTRAVENOUS injections , *MATERNAL-fetal exchange , *NARCOTICS , *QUESTIONNAIRES , *RESEARCH funding , *SHEEP , *PHARMACODYNAMICS - Abstract
Introduction: There are limited data on oxycodone pharmacokinetics during pregnancy and on fetal exposure after maternal administration. The present study describes the pharmacokinetics of intravenous (i.v.) oxycodone in pregnant sheep and fetal exposure after intravenous and epidural administration.Material and Methods: Ten pregnant sheep received 0.1 mg·kg-1 oxycodone intravenously, and blood samples were collected up to 24 hours. Seven days later, the ewes were randomized to receive 0.5 mg·kg-1 oxycodone intravenously (n = 5) or epidurally (n = 5) as a single bolus, before laparotomy for placement of catheters into the fetal superior vena cava and carotid artery. Paired maternal and fetal blood samples were taken when the fetal arterial catheter was in place and at the end of surgery. Maternal blood samples were taken up to 24 hours.Results: After 0.1 mg·kg-1 oxycodone intravenously, the median clearance was 5.2 L·h-1 ·kg-1 (range 4.6-6.2), but the volume of distribution varied between 1.5 and 4.7 L·kg-1 . The area under the curve was 17 h·ng·mL-1 (range 14-19) and the plasma concentration at 2 minutes 60 ng·mL-1 (range 50-74). Following administration of 0.5 mg·kg-1 intravenously or epidurally, oxycodone concentrations were similar in the maternal and the fetal plasma. Accumulation of oxymorphone in the fetus occurred; fetal-to-maternal ratios were 1.3-3.5 (median 2.1) in the i.v.-group and 0.9-3.0 (1.3) in the Epidural-group.Conclusions: We determined the pharmacokinetics of oxycodone in pregnant sheep. We showed accumulation of oxymorphone, which an active metabolite of oxycodone, in the fetus. Further studies in human pregnancies are required to evaluate the safety of oxycodone. [ABSTRACT FROM AUTHOR]- Published
- 2018
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15. Maturation of oxycodone pharmacokinetics in neonates and infants: Oxycodone and its metabolites in plasma and urine.
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Kokki, Merja, Heikkinen, Marja, Välitalo, Pyry, Hautajärvi, Heidi, Hokkanen, Juho, Pitkänen, Hanna, Sankilampi, Ulla, Ranta, Veli‐Pekka, and Kokki, Hannu
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OXYCODONE ,PHARMACOKINETICS ,PREMATURE infants ,NEWBORN infants ,VOLUMETRIC analysis - Abstract
Aims This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year-old infants. Methods Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg kg
−1 during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified. The unconjugated forms of these compounds were determined in urine collected after up to 24 or 48 h from 25 infants. Pharmacokinetics was determined using noncompartmental analysis and reported for six clinically relevant age groups based on postmenstrual age. Results Oxycodone pharmacokinetics changed markedly with patient age. Preterm neonates were found to have the highest pharmacokinetic variability out of the study population. In extremely preterm neonates ( n = 6) median of elimination half-life was 8.8 h (range 6.8-12.5), in preterm ( n = 11) 7.4 h (4.2-11.6), and in older neonates ( n = 22) 4.1 h (2.4-5.8), all of which were significantly longer than that in infants aged 6-24 months ( n = 12) 2.0 h (1.7-2.6). Median renal clearance was fairly constant in all age groups, whereas non-renal clearance markedly increased with age. Noroxycodone was the major metabolite in plasma and urine. Conclusions Oxycodone elimination is slower and pharmacokinetic variability more pronounced in neonates when compared to older infants. These findings highlight the importance of careful dose titration for neonates. [ABSTRACT FROM AUTHOR]- Published
- 2017
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16. Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe.
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Heikkinen, Emma M., Voipio, Hanna‐Marja, Laaksonen, Sakari, Haapala, Linnea, Räsänen, Juha, Acharya, Ganesh, Erkinaro, Tiina, Haapsamo, Mervi, Hautajärvi, Heidi, Kokki, Hannu, Kokki, Merja, and Heikkinen, Aki T.
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FENTANYL ,PHARMACOKINETICS ,TRANSDERMAL medication ,INTRAVENOUS therapy ,PREGNANCY in mammals ,SHEEP - Abstract
Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/hr were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intra-operative 2.5 μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra- and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep. [ABSTRACT FROM AUTHOR]
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- 2015
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17. Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children.
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Välitalo, Pyry, Kumpulainen, Elina, Manner, Minna, Kokki, Merja, Lehtonen, Marko, Hooker, Andrew C., Ranta, Veli-Pekka, and Kokki, Hannu
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CEREBROSPINAL fluid ,CONFIDENCE intervals ,NAPROXEN ,STRUCTURAL frame models ,DESCRIPTIVE statistics ,CHILDREN - Abstract
The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L /70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age. [ABSTRACT FROM PUBLISHER]
- Published
- 2012
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18. Intravenous Oxycodone for Pain Relief in the First Stage of Labour - Maternal Pharmacokinetics and Neonatal Exposure.
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Kokki, Merja, Franco, Maria Gonzalez, Raatikainen, Kaisa, Välitalo, Pyry, Sankilampi, Ulla, Heinonen, Seppo, Neuvonen, Pertti J., and Kokki, Hannu
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OXYCODONE ,ANALGESIA ,PHARMACOKINETICS ,LABOR pain (Obstetrics) ,NEWBORN infants ,FIRST stage of labor (Obstetrics) - Abstract
Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open-labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1 mg i.v., up to a cumulative dose of 5 mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half-life of 2.6 hr (range, 1.8-2.8). Oxycodone concentrations in the umbilical plasma 2.7 μg/l (0.3-14.5) were similar as in maternal plasma 2.4 (0.1-14.8) μg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half-life of i.v. oxycodone was significantly shorter than that reported in non-pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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19. Ketoprofen Pharmacokinetics, Efficacy, and Tolerability in Pediatric Patients.
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Kokki, Hannu
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MUSCULOSKELETAL system diseases , *NONSTEROIDAL anti-inflammatory agents , *PHARMACOKINETICS , *POSTOPERATIVE pain , *PREOPERATIVE care , *PEDIATRICS , *PAIN management , *DRUG efficacy - Abstract
The NSAID ketoprofen is used widely in the management of inflammatory and musculoskeletal conditions, pain, and fever in children and adults. Pharmacokinetic studies show that drug exposure after a single intravenous dose is similar in children and adults (after dose normalization), and thus similar mg/kg bodyweight dosing may be used in children and adults. Ketoprofen crosses the blood-brain barrier and therefore has the potential to cause central analgesic effects. Ketoprofen has been investigated in children for the treatment of pain and fever, pen- and postoperative pain, and inflammatory pain conditions. The results of four clinical trials in febrile conditions with the oral syrup formulation indicate that ketoprofen is as effective as acetaminophen (paracetamol) and ibuprofen, allowing children to rapidly return to daily activities with improvements in sleep quality and appetite. Studies of ketoprofen in the management of postoperative pain indicate that ketoprofen is a highly effective analgesic when administered perioperatively for a variety of surgical types, by a variety of routes, and whether given preoperatively or postoperatively. For adenoidectomy, intravenous ketoprofen provided superior postoperative analgesic efficacy compared with placebo. Analgesic efficacy was similar with intravenous, intramuscular, or rectal routes of administration, but oral administration just before surgery was inferior to intravenous administration in this setting. In patients undergoing a tonsillectomy, intravenous ketoprofen was superior to intravenous tramadol in terms of the need for postoperative rescue analgesia, but did not remove the need for rescue opioid therapy in these patients. Intravenous ketoprofen had superior postoperative analgesic efficacy to placebo when given as an adjuvant to epidural sufentanil analgesia after major surgery. Oral ketoprofen has shown efficacy in the treatment ofjuvenile rheumatoid arthritis. Ketoprofen is generally well tolerated in pediatric patients. Most of the adverse events reported are mild and transient, and are similar to those observed with other NSAIDs. Long-term tolerability has not yet been fully established in children, but data from three studies in >900 children indicate that oral ketoprofen is well tolerated when administered for up to 3 weeks after surgery. In conclusion, ketoprofen is effective and well tolerated in children for the control of post-surgical pain and for the control of pain and fever in inflammatory conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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20. Diclofenac readily penetrates the cerebrospinal fluid in children.
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Kokki, Hannu, Kumpulainen, Elina, Laisalmi, Merja, Savolainen, Jouko, Rautio, Jarkko, and Lehtonen, Marko
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DICLOFENAC , *CEREBROSPINAL fluid , *CYCLOOXYGENASE 2 , *PEDIATRIC surgery , *ANTI-inflammatory agents - Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans. WHAT THIS STUDY ADDS • Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg−1, sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h. AIMS The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children. METHODS A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg−1. Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection. RESULTS In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 μg l−1. At 5.5 h the CSF concentration was 0.1 μg l−1, and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 μg l−1 (range 70–272 μg l−1). No serious or unexpected adverse effects were reported. CONCLUSIONS Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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21. Paracetamol (Acetaminophen) Penetrates Readily Into the Cerebrospinal Fluid of Children After Intravenous Administration.
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Kumpulainen, Elina, Kokki, Hannu, Halonen, Toivo, Heikkinen, Maria, Savolainen, Jouko, and Laisalmi, Merja
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ACETAMINOPHEN , *CEREBROSPINAL fluid , *CHILDREN'S health , *CENTRAL nervous system , *INTRAVENOUS therapy , *FLUORESCENCE , *IMMUNOASSAY - Abstract
INTRODUCTION. The main action of paracetamol (acetaminophen) is presumed to be in the central nervous system. The central nervous system penetration of paracetamol has been described in children with intracranial pathologies but not in children with an intact blood-brain barrier. OBJECTIVE. We investigated the cerebrospinal fluid penetration of paracetamol in 32 healthy children, aged 3 months to 12 years, who were undergoing surgery in the lower body using spinal anesthesia. MATERIALS AND METHODS. In this open-label prospective study, children were given a single intravenous injection of paracetamol (15 mg/kg). Cerebrospinal fluid and venous blood samples were obtained between 5 minutes and 5 hours after injection. Paracetamol concentrations were determined from the cerebrospinal fluid and plasma by using a fluorescence polarization immunoassay. RESULTS. Paracetamol was detected in cerebrospinal fluid from the earliest sample at 5 minutes, although in this sample paracetamol concentration was below the limit of quantification of 1.0 mg/L. Subsequent paracetamol concentrations in cerebrospinal fluid ranged between 1.3 and 18 mg/L (median: 7.2 mg/L), plasma concentrations ranged between 2.4 and 33 mg/L, and cerebrospinal fluid/plasma ratios ranged between 0.06 and 2.0. The highest CSF paracetamol concentration was detected at 57 minutes. CONCLUSIONS. Paracetamol permeates readily into the cerebrospinal fluid of children. This fast and extensive transfer enables the rapid central analgesic and antipyretic action of intravenous paracetamol. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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22. Comparison of oxycodone pharmacokinetics after buccal and sublingual administration in children.
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Kokki, Hannu, Rasanen, Ilpo, Lasalmi, Merja, Lehtola, Sanna, Ranta, Veli-Pekka, Vanamo, Kari, Ojanperä4;, Ilkka, and Ojanperä, Ilkka
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OXYCODONE , *PHARMACOKINETICS , *ANALGESICS , *DRUG administration , *NARCOTICS , *PEDIATRIC pharmacology - Abstract
OBJECTIVE: We evaluated and compared the pharmacokinetics of two oral administration routes of oxycodone parenteral liquid (10 mg/mL) – single buccal and sublingual administration – in 30 generally healthy awake children, aged 6–91 months. METHODS: Two groups of children undergoing inpatient surgery were enrolled. In a randomised fashion, children received a single dose of oxycodone 0.2 mg/kg buccally (n = 15) or sublingually (n = 15). Regular blood samples were collected for up to 12 hours, and plasma was analysed for oxycodone, oxymorphone and noroxycodone using gas chromatography-mass spectrometry. RESULTS: Bioavailability was similar after administration at the two instillation sites. The area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) was 2400–8000 ng · min/mL (median 4200 ng · min/mL) in the buccal group and 2700–7900 ng · min/mL (median 5500 ng · min/mL) in the sublingual group. After buccal administration, maximum plasma concentration (Cmax) was 5.4–39 ng/mL (16 ng/mL) after buccal and 5.5–42 ng/mL (22 ng/mL) after sublingual administration. Twelve of the 15 children in both groups reached the oxycodone analgesic concentration of 12 ng/mL, which was sustained for 43–209 minutes (median 160 minutes) in the children with buccal oxycodone and for 32–262 minutes (median 175 minutes) in the children with sublingual oxycodone. The terminal elimination half-lives were closely similar in the two groups: 104–251 minutes (median 140 minutes) in the buccal group and 110–190 minutes (150 minutes) in the sublingual group. CONCLUSION: The results of this study show that in young children the absorption of oxycodone is similar after buccal and sublingual instillation. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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23. Cerebrospinal fluid distribution of ketoprofen after intravenous administration in young children.
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Mannila, Anne, Kokki, Hannu, Heikkinen, Marja, Laisalmi, Merja, Lehtonen, Marko, Louhisto, Hanna L., Järvinen, Tomi, Savolainen, Jouko, and Järvinen, Tomi
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NONSTEROIDAL anti-inflammatory agents , *DRUG metabolism , *CEREBROSPINAL fluid , *ANALGESICS , *INTRAVENOUS injections , *ANTI-inflammatory agents , *PHARMACOKINETICS - Abstract
Objective: The purpose of this study was to evaluate the cerebrospinal fluid (CSF) distribution of an NSAID, ketoprofen, in children. Ketoprofen concentrations were determined from the CSF, plasma and protein-free plasma samples.Methods: Children (n = 21), aged 13-94 months, were given intravenous ketoprofen (1 mg/kg) prior to surgery under spinal anaesthesia. Single venous blood and CSF samples from each patient were collected simultaneously 7-67 minutes after the drug administration. Ketoprofen concentrations in the samples were determined using gas chromatography-mass spectrometry.Results: Ketoprofen entered the CSF and was detectable in all samples. However, CSF delivery was limited; the ratio of ketoprofen concentration in CSF to plasma remained below 0.006 at all times. Ketoprofen was highly bound (> 98%) to plasma proteins. The free ketoprofen fraction was not in equilibrium with the CSF, and no clear peak drug concentration in the CSF was observed.Conclusion: This study shows that ketoprofen is able to enter the CSF of children, which enables central analgesic effects of ketoprofen. However, the slow distribution of ketoprofen into the CSF and the apparently low absolute concentrations has to be taken into account when central analgesic effects are desired. [ABSTRACT FROM AUTHOR]- Published
- 2006
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24. Population Pharmacokinetics of Oxycodone in Children 6 Months to 7 Years Old.
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El-Tahtawy, Ahmed, Kokki, Hannu, and Reidenberg, Bruce E.
- Abstract
Young children are often undertreated for pain. One barrier to effective pain treatment is understanding the pharmacokinetic behavior of analgesics in this age group. Oxycodone is a commonly prescribed opioid for severe pain, yet little is known about its pharmacokinetics in young children. This article used population pharmacokinetic modeling to synthesize pharmacokinetic data from several studies into a model. A single population model that described the observed pharmacokinetics was developed. The combined data were best described with a 2-compartment linear model with different first-order absorption rates depending on route of administration. Weight was found to significantly influence both clearance (CL) and volume of distribution (Vd). The following model adequately describes the population pharmacokinetic profile of oxycodone where absolute bioavailability (F) is estimated for each administration route: CL/F = 55×(body weight/70)0.87;V/F=86×(body weight/70)1.16.The interindividual coefficients of variation in CL and Vd were 20.2 and 19.7%, respectively. This finding confirms that the allometric scaling using the above model explained most of the variability in exposure observed among children. This model confirms using a weight-based dose for oxycodone without adjustment for age between 6 months and 7 years and is valuable for evaluating dosing schedules and dosing routes. [ABSTRACT FROM PUBLISHER]
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- 2006
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25. Pharmacokinetics of oxycodone after intravenous, buccal, intramuscular and gastric administration in children.
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Kokki, Hannu, Rasanen, Ilpo, Reinikainen, Matti, Suhonen, Pekka, Vanamo, Kari, Ojanperä, Ilkka, and Ojanperä, Ilkka
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PHARMACOKINETICS , *PARENTERAL therapy , *PARENTERAL solutions , *DRUG administration , *PATIENTS , *GAS chromatography - Abstract
Objective: To evaluate the pharmacokinetics of four administration routes of oxycodone parenteral liquid (10 mg/mL), single intravenous and intramuscular injections and buccal and gastric administration, in children.Patients and Participants: Forty generally healthy children, aged 6-93 months, undergoing inpatient surgery.Methods: After induction of anaesthesia, children received a single dose of oxycodone 0.1 mg/kg intravenously (n = 9), intramuscularly (n = 10), buccally (n = 11) or via an orogastric tube into the stomach (n = 10). Regular blood samples were collected up to 12 hours, and plasma was analysed for oxycodone using gas chromatography-mass spectrometry (limit of quantification 1 microg/L).Results: The peak drug concentration observed was 57-110 (mean 82) microg/L after intravenous administration, 23-54 (34) microg/L after intramuscular administration, 3.9-14 (9.8) microg/L after buccal administration and 1.7-15 (9.2) microg/L after gastric administration. The time to peak concentration was 2-30 (16) minutes in the intramuscular group, 30-480 (221) minutes in the buccal group and 60-360 (193) minutes in the gastric group. The terminal elimination half-lives were closely similar in the four groups: 124-208 (163) minutes in the intravenous group, 162-227 (150) minutes in the intramuscular group, 73-234 (150) minutes in the buccal group and 80-246 (147) minutes in the gastric group. Area under the concentration-time curve (AUC) was 5037-8954 (6612) microg x min/L in the intravenous group, 3084-5524 (4473) microg x min/L in the intramuscular group, 1444-5560 (3658) microg x min/L in the buccal group and 692-3843 (2436) microg x min/L in the gastric group. The estimated bioavailability (AUC/mean intravenous AUC) of intramuscular oxycodone was 0.47-0.84 (0.68), that of buccal oxycodone 0.22-0.84 (0.55) and that of gastric oxycodone 0.10-0.58 (0.37).Conclusion: The pharmacokinetics of intravenous oxycodone in children aged 6-93 months are fairly similar to those reported in adults. Intramuscular administration provides relatively constant drug absorption, but after buccal and gastric administration the interindividual variation in the rate and extent of absorption is large. [ABSTRACT FROM AUTHOR]- Published
- 2004
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26. Pharmacokinetics of intravenous and rectal ketoprofen in young children.
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Kokki, Hannu, Karvinen, Marko, and Suhonen, Pekka
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ANALGESICS , *PHARMACOKINETICS , *BIOAVAILABILITY , *CLINICAL trials , *COMPARATIVE studies , *HIGH performance liquid chromatography , *INTRAVENOUS injections , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *NONSTEROIDAL anti-inflammatory agents , *RECTAL medication , *RESEARCH , *TIME , *EVALUATION research , *CARBOCYCLIC acids - Abstract
Objective: To evaluate the relative bioavailabilities of ketoprofen after intravenous and rectal administration to young children.Design: Open-label prospective parallel-group study.Patients: Participants were 28 children aged 7 to 93 months.Methods: Eighteen children received a single intravenous injection of ketoprofen 1 mg/kg, and ten children, weight 16-24 kg, received a 25mg ketoprofen suppository. Venous blood samples were collected at selected times after administration, ranging from 2 minutes to 8 hours for the intravenous group and from 30 minutes to 8 hours for the suppository group. A validated high performance liquid chromatography method was used to measure plasma ketoprofen concentrations.Results: In the intravenous group, the maximum plasma concentration of ketoprofen ranged between 10.5 and 22.2 mg/L, and in the suppository group, following dose normalisation to 1 mg/kg of ketoprofen, between 3.8 and 7.4 mg/L. In the intravenous group, area under the concentration-time curve from zero to infinity ranged between 9.2 and 23.5 mg x h/L, and in the suppository group after dose normalisation between 8.8 and 12.9 mg x h/L. The bioavailability of ketoprofen from the suppository was about 73%. Volume of distribution was 0.04-0.10 L/kg in the intravenous group and 0.08-0.16 L/kg in the suppository group. The terminal half-life was comparable in both study groups, ranging between 0.7 and 3.0 hours in the intravenous group and between 1.2 and 2.9 hours in the suppository group.Conclusion: Absorption of ketoprofen after rectal administration is reasonably rapid and predictable. Because the bioavailability of rectal ketoprofen is also relatively high, a suppository may be used in children in whom the drug cannot be given intravenously or by mouth. [ABSTRACT FROM AUTHOR]- Published
- 2003
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27. Pharmacokinetics of ketoprofen following oral and intramuscular administration in young children.
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Kokki, Hannu, Tuomilehto, Henri, and Karvinen, Marko
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DRUG tablets ,ORAL drug administration ,THERAPEUTICS ,DRUG administration ,INTRAMUSCULAR injections ,CHROMATOGRAPHIC analysis ,PHARMACOKINETICS - Abstract
Objective: The pharmacokinetics of ketoprofen following intramuscular injection or oral tablet was determined in children aged 10–69 months. Methods: Ten children received a single intramuscular injection of 1 mg kg
–1 ketoprofen. Six children, weight 12–17 kg, received a 12.5-mg ketoprofen tablet and four children, weight 18–23 kg, received a 25-mg tablet. Venous blood samples were collected at 15 min and 30 min and 1, 2, 4, 6 and 8 h following drug dosing. Plasma ketoprofen levels were measured using a validated high-performance liquid chromatography method. Results: The maximal plasma concentration of ketoprofen ranged between 3.6 µg ml–1 and 7.4 µg ml–1 in the intramuscular group and, following a dose normalisation, between 2.8 µg ml–1 and 8.2 µg ml–1 in the tablet group (dose normalised for 1 mg kg–1 ). The rate and extent of absorption of ketoprofen were comparable after intramuscular and oral administration. The relative bioavailability of oral ketoprofen was about 100% of the intramuscular administration. The extrapolated area under the plasma concentration–time curve (AUC0– ∞ ) ranged between 8.8 µg ml–1 h and 14.6 µg ml–1 h in the intramuscular group and between 8.7 µg ml–1 h and 14.1 µg ml–1 h in the tablet group (dose-normalised AUC0– ∞ ). The terminal half-life was comparable in both study groups, ranging between 0.8 h and 2.2 h in the intramuscular group and between 0.9 h and 2.1 h in the tablet group. Conclusion: According to the pharmacokinetic properties determined in this study, there is no justification for using intramuscular administration in awake children. [ABSTRACT FROM AUTHOR]- Published
- 2001
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28. MATERNAL AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep.
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Hakomäki, Henriikka, Kokki, Hannu, Lehtonen, Marko, Räsänen, Juha, Voipio, Hanna-Marja, Ranta, Veli-Pekka, and Kokki, Merja
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FETAL anoxia , *TRANSDERMAL medication , *BUPRENORPHINE , *SHEEP , *PHARMACOKINETICS , *OPERATIVE surgery , *OPIOID peptides - Abstract
Buprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus. Pregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1 – 6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study. The transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13 – 27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102 – 269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples. The low transplacental passage of less than one fourth of the ewe's exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2021
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29. Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing.
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Hakomäki, Henriikka, Eskola, Sophia, Kokki, Hannu, Lehtonen, Marko, Räsänen, Juha, Laaksonen, Sakari, Voipio, Hanna-Marja, Ranta, Veli-Pekka, and Kokki, Merja
- Subjects
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SUBSTANCE abuse in pregnancy , *CENTRAL nervous system , *SHEEP breeding , *BUPRENORPHINE , *CEREBROSPINAL fluid , *SKIN permeability , *LAMBS , *SHEEP - Abstract
Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 – 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma -ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 µg/h dosing group, medians 65 – 122, than in the 20 µg/h group, medians 26 – 54. The subcutaneous injection (theoretical release rate 47.6 µg/h) produced higher concentrations than observed after 40 µg/h transdermal patch dosing. The median fetal/maternal concentration -ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8 – 13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs' plasma and CNS tissues two days postdelivery. Norbuprenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery. [Display omitted]. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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30. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach.
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Yamamoto, Yumi, Välitalo, Pyry A., Wong, Yin Cheong, Huntjens, Dymphy R., Proost, Johannes H., Vermeulen, An, Krauwinkel, Walter, Beukers, Margot W., Kokki, Hannu, Kokki, Merja, Danhof, Meindert, van Hasselt, Johan G.C., and de Lange, Elizabeth C.M.
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PHARMACOKINETICS , *TARGETED drug delivery , *CENTRAL nervous system , *DRUG development , *BLOOD-brain barrier , *ACTIVE biological transport - Abstract
Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin). The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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