What happens if you administer pregablin with a patient with low creatinine clearance?

Comment by InpharmD Researcher

Studies show gabapentinoids given to patients with renal impairment can result in altered mental status and falls if administered without dose adjustment.

Background

Gabapentin and pregabalin exhibit unique pharmacokinetic properties that pose challenges in achieving therapeutic concentrations, especially in patients with renal impairment. Neither drug undergoes hepatic metabolism; instead, they are primarily excreted unchanged through the urine, minimizing the risk of hepatic cytochrome P450-related drug-drug and drug-food interactions. Gabapentin's clearance is linearly correlated with creatinine clearance (CrCl) and may involve active tubular secretion via organic cation transporter-1 (OCT-1), though this is not fully clinically significant due to its primary filtration excretion. Pregabalin undergoes some tubular reabsorption, with a clearance rate lower than that of gabapentin. Both drugs require dose adjustments based on the degree of renal impairment. For instance, pregabalin maximum recommended dosages are altered based on CrCl values: 100 mg TID or 150 mg BID for CrCl 30-59 mL/min, 50 mg TID or 75 mg BID for CrCl 15-29 mL/min, 75 mg once daily for CrCl <15 mL/min, and 75-150 mg post-dialysis; gabapentin follows a similar adjustment strategy. Hemodialysis effectively removes about 35% of gabapentin and 50-60% of pregabalin, necessitating supplementary dosing post-treatment. Despite these dosing guidelines, most relevant pharmacokinetic studies have been conducted in healthy individuals, with limited data on clinical efficacy in patients with renal dysfunction. Therefore, while therapeutic dosing targets have been established for neuropathic pain, careful consideration of individual patient factors, such as side effect profiles and tolerability, alongside pharmacokinetic calculations, is critical for effective management in patients with chronic kidney disease. [1]

A 2018 clinical epidemiology study examined the association between the use of gabapentin and pregabalin and the risk of adverse outcomes in a substantial cohort of hemodialysis patients. The researchers utilized the US Renal Data System to identify 140,899 Medicare-covered adults undergoing hemodialysis with Part D coverage in 2011. Gabapentin and pregabalin were modeled as separate time-varying exposures to evaluate their association with time to first emergency room visit or hospitalization due to altered mental status, fall, and fracture. The risk was assessed according to daily dose categories: for pregabalin (0-100 and >100 mg). Notably, 68% of the users were diagnosed with neuropathic pain, pruritus, or restless legs syndrome. Results found that increased doses of pregabalin were associated with greater rates of altered mental status, falls, and fractures. Specifically, when comparing no pregabalin use to low-dose (0–100 mg) and high-dose (>100 mg) use, the incidence of altered mental status was 15, 26, and 25 per 100 person-years, respectively. For falls, the incidence was seven, ten, and 14 per 100 person-years, respectively, and for fractures, it was four, five, and five per 100 person-years, respectively. Both low-dose (HR 1.51; 95% CI, 1.32 to 1.74) and high-dose pregabalin (HR 1.46; 95% CI, 1.24 to 1.71) were associated with a higher hazard of altered mental status. Only high-dose pregabalin was linked to an increased hazard of falls (HR 1.68; 95% CI, 1.36 to 2.08), while neither dose significantly increased fracture risk. Additionally, a shorter duration of pregabalin exposure (<30 days) was linked to a significantly higher hazard of altered mental status (HR 1.29; 95% CI, 1.07 to 1.54) and falls (HR 1.32; 95% CI, 1.02 to 1.72) compared to longer durations. The findings were consistent even in sensitivity analyses restricted to low-income subsidy recipients. These results underscore the caution needed when prescribing pregabalin, particularly at higher doses, due to the associated increased risks of these adverse outcomes. [2]

References:

[1] Raouf M, Atkinson TJ, Crumb MW, Fudin J. Rational dosing of gabapentin and pregabalin in chronic kidney disease. J Pain Res. 2017;10:275-278. Published 2017 Jan 27. doi:10.2147/JPR.S130942
[2] Ishida JH, McCulloch CE, Steinman MA, Grimes BA, Johansen KL. Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients. J Am Soc Nephrol. 2018;29(7):1970-1978. doi:10.1681/ASN.2018010096

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What happens if you administer pregablin with a patient with low creatinine clearance?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Pharmacokinetics of Pregabalin in Subjects with Various Degrees of Renal Function

Design

Open-label, parallel-group study

N= 38

Objective

To determine the single-dose pharmacokinetics of pregabalin in subjects with various degrees of renal function, determine the relationship between pregabalin clearance and estimated creatinine clearance (CrCl), and measure the effect of hemodialysis on plasma levels of pregabalin

Study Groups

CrCl < 30 mL/min (n= 8)

CrCl 30-50 mL/min (n= 5)

CrCl 50-80 mL/min (n= 7)

CrCl > 80 mL/min (n= 6)

Hemodialysis (n= 12)

Inclusion Criteria

Subjects with preselected degrees of renal function based on CrCl( as determined by the Cockcroft and Gault equation); aged 18-75 years and weigh between 45-110 kg

Exclusion Criteria

Current evidence or history of drug or alcohol abuse or clinically significant respiratory, cardiovascular, hepatic, neurologic, gastrointestinal, or psychiatric disease; prior history of an adverse reaction to any antiepileptic drug

Methods

Each subject received a single 50 mg dose of pregabalin orally (two 25 mg capsules). Pregabalin concentrations were measured using liquid chromatographic methods. Pharmacokinetic parameters were evaluated by noncompartmental methods. Blood and urine samples were collected at various intervals based on renal function category.

Duration Not specified
Outcome Measures

Primary: Pregabalin pharmacokinetics in relation to renal function

Secondary: Effect of hemodialysis on pregabalin plasma levels

Baseline Characteristics   CrCl > 80 mL/min (n= 6) CrCl 51-80 mL/min (n= 7) CrCl 30-50 mL/min (n= 5) CrCl < 30 mL/min (n= 8) Hemodialysis (n= 12)

Mean Age, Years (Range)

53 (46-64) 57 (44-74) 64 (38-75) 53 (40-73) 48 (30-66)

Mean Weight, kg (Range)

79.5 (70.5-91.6) 83.0 (61.6-105.0) 89.2 (61.6-105.9) 74.7 (44.5-92.7) 93.7 (73.2-115.5)
Results   CrCl > 60 mL/min (n= 11) CrCl 30-60 mL/min (n= 7) CrCl 15-29 mL/min (n= 7) CrCl < 15 mL/min (n= 1) Hemodialysis Patients (n= 12)
Cmax, µg/mL 1.86 1.53 1.90 1.69 1.24
tmax, h 1.00 1.29 1.93 1.00 3.18
AUC0-∞, µg•h/mL 15.9 28.2 52.3 101 94.6
t1/2, h 9.11 16.7 25.0 48.7 54.7
Adverse Events

Dizziness, somnolence, and asthenia occurred sporadically. No serious adverse events were recorded

Study Author Conclusions

Pregabalin dosage adjustment should be considered for patients with CrCl values of < 60 mL/min. Supplemental doses of pregabalin may be required for patients supported by chronic hemodialysis treatment after each hemodialysis treatment to maintain steady-state plasma pregabalin concentrations within desired ranges.

Critique

The study provides valuable insights into the pharmacokinetics of pregabalin in patients with varying degrees of renal function, which is crucial for dose adjustment. However, the study's open-label design and small sample size may limit the generalizability of the findings. Additionally, the study did not include a long-term follow-up to assess the clinical outcomes of the dosing recommendations.

 

References:

Randinitis EJ, Posvar EL, Alvey CW, Sedman AJ, Cook JA, Bockbrader HN. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43(3):277-283. doi:10.1177/0091270003251119

 

Evaluation of Gabapentin and Pregabalin Use in Hospitalized Patients With Decreased Kidney Function

Design

Single-center retrospective cohort study

N= 286

Objective

To determine whether patients with decreased creatinine clearance (CrCl) experienced increased frequency of AEs related to gabapentinoid dose at hospital admission

Study Groups

Gabapentin (n= 234)

Pregabalin (n= 52)

Inclusion Criteria

Adults (≥18 years of age) with gabapentin or pregabalin prescription documentation on admission medication reconciliation documents and at least one serum creatinine measurement during hospital stay

Exclusion Criteria

Pregnant, immunosuppressed, admitted for opioid or alcohol dependence, and withdrawal, or missing information required to calculate CrCl

Methods

This was a retrospective cohort study conducted at a single-center in California. Patients were grouped based on estimated CrCl of ≥60 mL/min or <60 mL/min. Subgroup analysis included CrCl of 15 to 29 mL/min and <15 mL/min. Appropriateness of gabapentinoid prescription was evaluated based on CrCl and manufacturer dosing guidance. Incidence of AEs related to gabapentinoid use was collected and recorded. Concomitant opioid or psychiatric medications were also recorded.

Duration

January 2018 to June 2019

Outcome Measures

Primary: Appropriateness of gabapentinoid prescription based on CrCl

Secondary: Incidence of AEs related to gabapentinoids, influence of concomitant opioid and psychiatric prescriptions

Baseline Characteristics  

CrCl ≥60 mL/min (n= 167)

CrCl <60 mL/min (n= 119)
Age, years (IQR) 59 (51-67) 70 (61-78)
Females 86 (51.5%) 66 (55.5%)
Height, cm (IQR) 172.7 (162.6-180.3) 167.6 (160-176.5)
Weight, kg (IQR) 94.4 (76.9-113.4) 81.8 (68.5-101.7)
Hypertension 114 (68.3%) 97 (81.5%)
Diabetes 86 (51.5%) 78 (65.5%)
Psychiatric medications 142 (85) 86 (72.3%)
Opioid medications 86 (51.5) 67 (56.3%)
Results  

CrCl ≥60 mL/min (n= 137)

CrCl <60 mL/min (n= 97)
Patients with dose above recommended range for CrCl 1 (0.7%) 33 (34%)
Patients with dose above recommended range for CrCl and concomitant opioid medications 1 (0.7%) 20 (20.6%)
Patients with dose above recommended range for CrCl and concomitant psychiatric medications 0 26 (26.8%)

Patients with creatinine clearance (CrCl) ≥60 mL/min were prescribed higher average total daily doses (TDDs) compared to those with lower CrCl. However, for patients with CrCl <30 mL/min, no significant differences were observed in the average and median TDDs between those with CrCl 15-29 mL/min and CrCl <15 mL/min. A significant portion of patients with CrCl <60 mL/min received doses higher than manufacturer recommendations: 34% for gabapentin and 22.7% for pregabalin. Notably, nearly half of the gabapentin recipients with CrCl between 15 to 29 mL/min and <15 mL/min received excessively high doses, and 80% of patients receiving pregabalin with CrCl <15 mL/min were also overdosed.

A particularly concerning finding was that inappropriate gabapentin dosing was prevalent among those concurrently using opioids (61.8%) and psychiatric medications (76.5%). For pregabalin, 100% of those receiving inappropriate doses were on opioids, and 80% were on psychiatric medications.

Adverse Events

A significant increase in recorded falls (p= 0.029) was identified in patients with a CrCl <60 mL/min.

Adverse events (AEs), particularly falls, were significantly higher among patients with CrCl <60 mL/min who used concomitant opioid and psychiatric medications. This group showed increased occurrences of hypotension, confusion, and weakness. A post-hoc subgroup analysis that excluded patients with acute kidney injury (AKI) supported these findings, showing similar trends in baseline characteristics, TDD, and AE incidence.

Study Author Conclusions

Patients with a CrCl <60 mL/min were frequently prescribed inappropriately high doses of gabapentinoids. The relationship between gabapentinoid dosing, kidney function, and the incidence of gabapentinoid-related AEs at hospital admission requires larger, multicentre studies.

Critique

This study was limited by its retrospective nature, single-center design, and lack of power calculation for primary outcomes. Significant differences in baseline characteristics could have been confounders for the frequency of AEs. The study did not examine the potential influence of concomitant antihypertensive medications on the incidence of hypotension. Generalizability is limited outside of this patient population and prescribing practices.

 

References:

Knowles GM, LaFleur GE, Churchwell MD. Evaluation of Gabapentin and Pregabalin Use in Hospitalized Patients With Decreased Kidney Function. J Pharm Technol. 2024;40(1):30-36. doi:10.1177/87551225231217906