&lt;p&gt;Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets&lt;/p&gt;

Hwang, Jun Gi; Yu, Kyung‐Sang; Lee, Seung Hwan

doi:10.2147/dddt.s233732

Cited by 9 publications

(16 citation statements)

References 15 publications

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“…Following the administration of upadacitinib 30 mg once daily, rosuvastatin and atorvastatin C max and AUC were slightly (11%-33%) lower when the statins were administered alone. This relatively small effect is within the reported intrasubject variability in rosuvastatin and atorvastatin plasma exposures (≈25% and 45%, respectively) 29,32 ; therefore, it is not expected to be of clinical relevance. Additionally, the approved doses of rosuvastatin (5-40 mg) and atorvastatin (10-80 mg) are at 5-to 40-fold the estimated dose that results in 50% of the maximum effect and the pharmacologic effect of the statins is estimated to be near the plateau at this therapeutic dose range.…”

Section: Discussionsupporting

confidence: 66%

“…During period 2 of both parts of this study, upadacitinib 30 mg was dosed alone once daily for 10 days and rosuvastatin (in part 1) or atorvastatin (in part 2) was administered 1 hour following upadacitinib dosing on day 7. Part 1 was conducted in 12 healthy subjects, and part 2 was conducted in 24 healthy subjects, given the higher within‐subject variability in atorvastatin pharmacokinetics compared to rosuvastatin 29,30 . All study drugs were administered orally with ≈240 mL of water under nonfasting conditions.…”

Section: Methodsmentioning

confidence: 99%

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Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects

Mohamed

Coppola

Tian

et al. 2021

Clinical Pharm in Drug Dev

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This phase 1, 2-part, 2-period, open-label, drug-drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once-daily doses of upadacitinib extended-release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to infinity (AUC inf ) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin C max and AUC inf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The C max and AUC inf of the active metabolite ortho-hydroxyatorvastatin remained unchanged. Administration of a single 5-mg dose of rosuvastatin or a single 10-mg dose of atorvastatin had no relevant effect on upadacitinib C max or area under the plasma concentrationtime curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.

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Section: Discussionsupporting

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects

Mohamed

Coppola

Tian

et al. 2021

Clinical Pharm in Drug Dev

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“…For drugs with an expected within-subject variability greater than 30%, either a partially or fully replicated design is proposed for the trials [ 25 ]. Fimasartan is considered a highly variable drug; therefore, a replicated study design is recommended [ 26 27 28 29 ]. Based on the recommendation, this study was designed in a three-period, partially replicated, crossover study design.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects

Jung

Lee

et al. 2021

Transl Clin Pharmacol

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For the treatment of hypertension, fixed-dose combinations (FDCs) of antihypertensive drugs can provide complementary benefits from improved compliance and cost-effectiveness compared with loose combinations of corresponding drugs. A new FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg is undergoing clinical development. A randomized, open-label, single-dose, 3-period, 3-sequence, partially replicated crossover phase 1 study was conducted to compare the pharmacokinetics (PKs) between the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a loose combination of a dual-combination FDC (fimasartan/amlodipine 60/10 mg) and hydrochlorothiazide 25 mg. Sixty healthy subjects were randomized, and 55 subjects completed the study. Serial blood samples were collected, and plasma concentrations of fimasartan, amlodipine and hydrochlorothiazide were measured to analyze PK parameters. The PK profiles of the FDC were similar to those of the loose combinations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to loose combinations for the maximum plasma concentration (C max ) and area under the curve until the last measurable time point (AUC last ) were within the conventional bioequivalent range of 0.80 to 1.25. The GMRs and 90% CIs of fimasartan, amlodipine and hydrochlorothiazide were 1.0163 (0.8681–1.1898), 0.9595 (0.9256–0.9946), and 1.1294 (1.0791–1.1821) for C max and 1.0167 (0.9347–1.1059), 0.9575 (0.9317–0.9841), and 1.0561 (1.0170–1.0967) for AUC last , respectively. Both the FDC and loose combinations were well tolerated. In conclusion, the FDC of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg showed similar PK profiles to those of the corresponding loose combination, and both treatments were well tolerated.

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“…31 , 32 , 33 , 34 Lins et al established mean half‐lives of 11.5 and 10.9 h for ATR after administering high doses (40 mg or 80 mg, respectively). 35 The proposed reasons for these differences are the evaluation of ATR+ATRL and ATR+MET, the use of a single‐compartment model, and heavily relying on early sample collection.…”

Section: Discussionmentioning

confidence: 99%

A pharmacokinetics‐based approach to the monitoring of patient adherence to atorvastatin therapy

Karvaly

Karádi

Vincze

et al. 2021

Pharmacology Res & Perspec

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The inadequate adherence of patients whose hyperlipidemia is treated with atorvastatin (ATR) to medical instructions presents a serious health risk. Our aim was to develop a flexible approach based on therapeutic drug monitoring (TDM), nonparametric population pharmacokinetic modeling, and Monte Carlo simulation to differentiate adherent patients from partially and nonadherent individuals in a nonrandomized, unicentric, observational study. Sixty‐five subjects were enrolled. Nonparametric, mixed‐effect population pharmacokinetic models of the sums of atorvastatin and atorvastatin lactone concentrations (ATR+ATRL) and of the concentrations of the acid and lactone forms of ATR and its 2‐ and 4‐hydroxylated pharmacologically active metabolites (ATR+MET) were elaborated by including the TDM results obtained in 128 samples collected from thirty‐nine subjects. Monte Carlo simulation was performed based on the elaborated models to establish the probabilities of attaining a specific ATR+ATRL or ATR+MET concentration in the range of 0.002–10 nmol (mg dose) −1 L −1 at 1–24 h postdose by adherent, partially adherent, and nonadherent patients. The results of the simulations were processed to allow the estimation of the adherence of further 26 subjects who were phlebotomized at sampling times of 2–20 h postdose by calculating the probabilities of attaining the ATR+ATRL and ATR+MET concentrations measured in these subjects in adherent, partially adherent, and nonadherent individuals. The best predictive values of the estimates of adherence could be obtained with sampling at early sampling times. 61.54% and 38.46% of subjects in the adherence testing set were estimated to be fully and partially adherent, respectively, while in all cases the probability of nonadherence was extremely low. The evaluation of patient adherence to ATR therapy based on pharmacokinetic modeling and Monte Carlo simulation has important advantages over the collection of trough samples and the use of therapeutic ranges.

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<p>Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets</p>

Cited by 9 publications

References 15 publications

Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects

Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects

Pharmacokinetic comparison between a fixed-dose combination of fimasartan/amlodipine/hydrochlorothiazide 60/10/25 mg and a corresponding loose combination of fimasartan/amlodipine 60/25 mg and hydrochlorothiazide 25 mg in healthy subjects

A pharmacokinetics‐based approach to the monitoring of patient adherence to atorvastatin therapy

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